U.S. patent number 8,921,378 [Application Number 14/112,727] was granted by the patent office on 2014-12-30 for androgen receptor modulating carboxamides.
This patent grant is currently assigned to Orion Corporation. The grantee listed for this patent is Terhi Heikkinen, Arja Karjalainen, Arputharaj Ebenezer Martin, Anu Moilanen, Pranab Kumar Patra, Rathna Durga Ramasubramanian, Harri Salo, Olli Tormakangas, Anniina Vesalainen, Gerd Wohlfahrt. Invention is credited to Terhi Heikkinen, Arja Karjalainen, Arputharaj Ebenezer Martin, Anu Moilanen, Pranab Kumar Patra, Rathna Durga Ramasubramanian, Harri Salo, Olli Tormakangas, Anniina Vesalainen, Gerd Wohlfahrt.
United States Patent |
8,921,378 |
Tormakangas , et
al. |
December 30, 2014 |
**Please see images for:
( Certificate of Correction ) ** |
Androgen receptor modulating carboxamides
Abstract
Compounds of formula (I) or (II) ##STR00001## wherein R.sub.x,
R.sub.z, R.sub.9, R.sub.10, R.sub.14, R.sub.14', R.sub.15,
R.sub.15', A and B are as defined in the claims and
pharmaceutically acceptable salts and esters thereof, are
disclosed. The compounds possess utility as tissue-selective
androgen receptor modulators (SARM) and are useful as medicaments
in the treatment of prostate cancer and other AR dependent
conditions and diseases where AR antagonism is desired.
Inventors: |
Tormakangas; Olli (Turku,
FI), Wohlfahrt; Gerd (Helsinki, FI), Salo;
Harri (Turku, FI), Ramasubramanian; Rathna Durga
(Turku, FI), Patra; Pranab Kumar (Noida,
IN), Martin; Arputharaj Ebenezer (Noida,
IN), Heikkinen; Terhi (Lieto, FI),
Vesalainen; Anniina (Paimio, FI), Moilanen; Anu
(Turku, FI), Karjalainen; Arja (Espoo,
FI) |
Applicant: |
Name |
City |
State |
Country |
Type |
Tormakangas; Olli
Wohlfahrt; Gerd
Salo; Harri
Ramasubramanian; Rathna Durga
Patra; Pranab Kumar
Martin; Arputharaj Ebenezer
Heikkinen; Terhi
Vesalainen; Anniina
Moilanen; Anu
Karjalainen; Arja |
Turku
Helsinki
Turku
Turku
Noida
Noida
Lieto
Paimio
Turku
Espoo |
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A |
FI
FI
FI
FI
IN
IN
FI
FI
FI
FI |
|
|
Assignee: |
Orion Corporation (Espoo,
FI)
|
Family
ID: |
46125469 |
Appl.
No.: |
14/112,727 |
Filed: |
April 20, 2012 |
PCT
Filed: |
April 20, 2012 |
PCT No.: |
PCT/FI2012/000022 |
371(c)(1),(2),(4) Date: |
December 18, 2013 |
PCT
Pub. No.: |
WO2012/143599 |
PCT
Pub. Date: |
October 26, 2012 |
Prior Publication Data
|
|
|
|
Document
Identifier |
Publication Date |
|
US 20140094474 A1 |
Apr 3, 2014 |
|
Foreign Application Priority Data
|
|
|
|
|
Apr 21, 2011 [IN] |
|
|
570/KOL/2011 |
|
Current U.S.
Class: |
514/259.1 |
Current CPC
Class: |
C07D
401/14 (20130101); C07D 403/04 (20130101); A61P
5/28 (20180101); C07D 403/12 (20130101); C07D
471/04 (20130101); C07D 487/04 (20130101); C07D
413/14 (20130101); C07D 401/04 (20130101); C07D
513/04 (20130101); C07D 231/14 (20130101); A61P
35/00 (20180101); C07D 413/12 (20130101); C07D
403/14 (20130101); A61P 43/00 (20180101) |
Current International
Class: |
A61K
31/519 (20060101) |
Field of
Search: |
;514/259.1 |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
|
|
|
|
|
|
|
0 100 172 |
|
Feb 1984 |
|
EP |
|
1 790 640 |
|
May 2007 |
|
EP |
|
WO 03/057669 |
|
Jul 2003 |
|
WO |
|
WO 2004/099188 |
|
Nov 2004 |
|
WO |
|
WO 2006/124118 |
|
Nov 2006 |
|
WO |
|
WO 2006/133567 |
|
Dec 2006 |
|
WO |
|
WO 2007/029035 |
|
Mar 2007 |
|
WO |
|
WO 2007/056155 |
|
May 2007 |
|
WO |
|
WO 2008/062878 |
|
May 2008 |
|
WO |
|
WO 2008/124000 |
|
Oct 2008 |
|
WO |
|
WO 2009/028543 |
|
Mar 2009 |
|
WO |
|
WO 2009/055053 |
|
Apr 2009 |
|
WO |
|
WO 2011/051540 |
|
May 2011 |
|
WO |
|
Other References
Benckova, M. et al, "Disubstituted Ureas of the 5-R-2-Furylethylene
Type," Chemical Papers, 50(3): 148-150 (Jan. 1, 1996). cited by
applicant .
Database Registry, Chemical Abstracts Service,
N-[2-(2,5-dimethyl-1-phenyl-1H-pyrrol-3-yl)ethyl]-4-phenyl-1-piperazineca-
rboxamide, XP002623901 (Mar. 2, 2007). cited by applicant .
Database Registry, Chemical Abstracts Service,
1-cycloheptyl-N-[2-[3-(2-methylphenyl)-1-pyrrolidinyl]ethyl]-1H-1,2,3-Tri-
azole-4-carboxamide, XP002623902 (Nov. 2, 2008). cited by applicant
.
Database Registry, Chemical Abstracts Service,
N-[2-[5-(2-nitrophenyl)-2-furanyl]ethenyl]-4-morpholinecarboxamide,
XP002623903 (Aug. 28, 2001). cited by applicant .
English Abstract for WO 2008/062878, Basic Derwent Week: 200867
(2012). cited by applicant .
International Search Report for International Application No.
PCT/FI2010/000065, mailed Mar. 17, 2011. cited by applicant .
Narayanan, R. et al, "Selective androgen receptor modulators in
preclinical and ciinical development," Nuclear Receptor Signaling,
6:1-26 (2008). cited by applicant .
Copending U.S. Appl. No. 13/504,511. cited by applicant .
Office Action dated Nov. 27, 2013, from copending U.S. Appl. No.
13/504,511. cited by applicant.
|
Primary Examiner: Shiao; Rei-Tsang
Assistant Examiner: Stone; Christopher R
Attorney, Agent or Firm: Finnegan, Henderson, Farabow,
Garrett & Dunner, LLP
Claims
The invention claimed is:
1. A compound of formula (I) or (II) ##STR00012## wherein ring A is
any one of the following groups or tautomers thereof ##STR00013##
wherein R.sub.X is halogen or CF.sub.3; R.sub.X is hydrogen or
halogen; R.sub.1 is hydroxy C.sub.3-7 alkyl, imidazolyl or
--R.sub.AOC(O)--R.sub.B; R.sub.A is C.sub.1-7 alkyl; R.sub.B is
C.sub.1-7 alkyl, hydroxy C.sub.1-7 alkyl or carboxy C.sub.1-7
alkyl; R.sub.2 is C.sub.1-7 alkyl, C.sub.2-7 alkenyl, C.sub.3-7
cycloalkyl, C.sub.3-7 cycloalkyl C.sub.1-7 alkyl, methylpyrazolyl
or pyrimidinyl; R.sub.3 is halogen or pyridinyl; R.sub.4 is
pyridinyl; R.sub.5 is C.sub.1-7 alkyl, C.sub.2-7 alkenyl, C.sub.3-7
cycloalkyl, C.sub.3-7 cycloalkyl C.sub.1-7 alkyl, cyano, hydroxy
C.sub.1-7 alkyl, oxo C.sub.1-7 alkyl, halogen or methylpyrazolyl;
R.sub.6 is C.sub.1-7 alkyl, C.sub.2-7 alkenyl, C.sub.3-7
cycloalkyl, C.sub.3-7 cycloalkyl C.sub.1-7 alkyl, hydroxy, hydroxy
C.sub.1-7 alkyl, cyano C.sub.1-7 alkyl or C.sub.1-7 alkoxycarbamoyl
C.sub.1-7 alkyl; R.sub.7 is hydroxy C.sub.4 alkyl; R.sub.8 is
halogen, C.sub.2-7 alkyl, C.sub.2-7 alkenyl, C.sub.3-7 cycloalkyl,
C.sub.3-7 cycloalkyl C.sub.1-7 alkyl, cyano, carboxy, oxo C.sub.1-7
alkyl, halo C.sub.1-7 alkyl, hydroxy C.sub.1-7 alkyl,
tetrahydro-2H-thiopyran or --C(O)--NHR.sub.20; R.sub.9 is hydrogen,
hydroxy, halogen, nitro, amino, cyano, oxo, C.sub.1-7 alkyl,
C.sub.2-7 alkenyl, C.sub.3-7 cycloalkyl, C.sub.1-7 alkoxy, halo
C.sub.1-7 alkyl, hydroxy C.sub.1-7 alkyl, cyano C.sub.1-7 alkyl,
amino C.sub.1-7 alkyl, oxo C.sub.1-7 alkyl, C.sub.1-7 alkoxy
C.sub.1-7 alkyl, C.sub.1-7 alkylamino, hydroxy C.sub.1-7
alkylamino, C.sub.1-7 alkoxy C.sub.1-7 alkylamino, C.sub.1-7
alkylamino C.sub.1-7 alkyl, hydroxy C.sub.1-7 alkylamino C.sub.1-7
alkyl, hydroxyimino C.sub.1-7 alkyl, C.sub.1-7 alkoxycarbamoyl
C.sub.1-7 alkyl, --C(O)R.sub.11, --OC(O)R.sub.17,
--NH--C(O)R.sub.18--NH--SO.sub.2--R.sub.19 or an optionally
substituted 5-12 membered carbocyclic or heterocyclic ring, each
group linked to B-ring via a bond or via a C.sub.1-7 alkylene
linker; R.sub.10 is hydrogen, halogen, C.sub.1-7 alkyl, C.sub.2-7
alkenyl, C.sub.3-7 cycloalkyl, C.sub.3-7 cycloalkyl C.sub.1-7
alkyl, oxo, hydroxy C.sub.1-7 alkyl, oxo C.sub.1-7 alkyl or an
optionally substituted 5 or 6 membered carbocyclic or heterocyclic
ring; R.sub.11 is hydrogen, hydroxy, C.sub.1-7 alkyl, hydroxy
C.sub.1-7 alkyl, C.sub.2-7 alkenyl, C.sub.3-7 cycloalkyl, halo
C.sub.1-7 alkyl, C.sub.1-7 alkoxy, NR.sub.12R.sub.13, or an
optionally substituted 5-12 membered carbocyclic or heterocyclic
ring; R.sub.12 is hydrogen, C.sub.1-7 alkyl, C.sub.2-7 alkenyl,
C.sub.3-7 cycloalkyl, C.sub.3-7 cycloalkyl C.sub.1-7 alkyl,
C.sub.1-7 alkoxy, hydroxy C.sub.1-7 alkyl, amino C.sub.1-7 alkyl or
C.sub.1-7 alkyl amino C.sub.1-7 alkyl; R.sub.13 is hydrogen or
C.sub.1-7 alkyl; R.sub.14 and R.sub.15 are, independently, hydrogen
or C.sub.1-7 alkyl; R.sub.14' and R.sub.15' are, independently,
hydrogen or C.sub.1-7 alkyl, or R.sub.14' and R.sub.15' together
form a bond; R.sub.17 is C.sub.1-7 alkyl, C.sub.2-7 alkenyl,
C.sub.3-7 cycloalkyl, C.sub.3-7 cycloalkyl C.sub.1-7 alkyl,
C.sub.1-7 alkoxy, amino C.sub.1-7 alkyl, C.sub.1-7 alkylamino or
C.sub.1-7 alkylamino C.sub.1-7 alkyl; R.sub.18 is C.sub.1-7 alkyl,
C.sub.2-7 alkenyl, C.sub.3-7 cycloalkyl, C.sub.3-7 cycloalkyl
C.sub.1-7 alkyl, amino C.sub.1-7 alkyl, C.sub.1-7 alkylamino or
C.sub.1-7 alkylamino C.sub.1-7 alkyl; R.sub.19 is C.sub.1-7 alkyl,
C.sub.2-7 alkenyl, C.sub.3-7 cycloalkyl or C.sub.3-7 cycloalkyl
C.sub.1-7 alkyl; R.sub.20 is hydrogen, C.sub.1-7 alkyl, C.sub.2-7
alkenyl, C.sub.3-7 cycloalkyl, C.sub.3-7 cycloalkyl C.sub.1-7 alkyl
or C.sub.1-7 alkoxy; R.sub.21 is cyano C.sub.1-7 alkyl or, in case
R.sub.x is CF.sub.3, R.sub.21 can also be hydroxy C.sub.1-7 alkyl;
R.sub.22 is hydroxy C.sub.1-7 alkyl; R.sub.23 is C.sub.1-7 alkyl or
hydroxy C.sub.1-7 alkyl; R.sub.24 is hydroxy, halogen or C.sub.1--,
alkoxy; ring B is chosen from any one of the following groups and
tautomers thereof ##STR00014## ##STR00015## ##STR00016##
##STR00017## or pharmaceutically acceptable salts thereof; with the
proviso that the compound of formula (II) is not any of the
following compounds:
(S)-3-acetyl-N-(1-(3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)pr-
opan-2-yl)-1H-pyrazole-5-carboxamide;
(S)--N-(1-(3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-y-
l)-1-(pyridin-4-yl)-1H-pyrazole-3-carboxamide;
(S)--N-(1-(3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-y-
l)-1-(2-fluoroethyl)-2-methyl-1H-imidazole-4-carboxamide;
(S)--N-(1-(3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-y-
l)-3-(1H-imidazol-4-yl)-1,2,4-oxadiazole-5-carboxamide;
(S)-5-acetyl-N-(1-(3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)pr-
opan-2-yl)isoxazole-3-carboxamide;
N--((S)-1-(3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-y-
l)-5-(1-hydroxyethyl)isoxazole-3-carboxamide;
(S)-5-acetyl-N-(2-(3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)pr-
opyl)isoxazole-3-carboxamide;
(S)--N-(2-(3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propyl)-2--
methyl-1H-imidazole-4-carboxamide;
N--((S)-1-(3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-y-
l)-3-(1-hydroxyethyl)-1H-pyrazole-5-carboxamide;
(R)--N-(1-(3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-y-
l)-2-methyl-1H-imidazole-4-carboxamide;
(S)--N-{1-[3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl]propan-2-y-
l}-2-methyl-1H-imidazole-4-carboxamide;
(S)--N-{1-[3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl]propan-2-y-
l}-1-methyl-1H-imidazole-4-carboxamide;
(S)--N-(1-(3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-y-
l)-3H-imidazo[4,5-b]pyridine-5-carboxamide;
(S)--N-(1-(3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-y-
l)-2-(pyridin-3-yl)thiazole-4-carboxamide;
(S)--N-(1-(3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-y-
l)-1-(pyridin-3-yl)-1H-pyrazole-3-carboxamide;
(S)--N-(1-(3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-y-
l)-2-methyl-1-(3-oxobutyl)-1H-imidazole-4-carboxamide;
(S)--N-(1-(3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-y-
l)-1-(3-hydroxy-3-methylbutyl)-2-methyl-1H-imidazole-4-carboxamide;
(S)--N-(1-(3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-y-
l)imidazo[1,2-a]pyridine-2-carboxamide;
(S)--N-(1-(3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-y-
l)-1-(pyridin-3-yl)-1H-imidazole-4-carboxamide;
(S)--N-(1-(3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-y-
l)-2-(2-hydroxypropan-2-yl)oxazole-4-carboxamide;
(S)--N-(1-(3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-y-
l)imidazo[1,2-a]pyrimidine-2-carboxamide;
(S)--N-(1-(3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-y-
l)-3-fluoroimidazo[1,2-a]pyridine-2-carboxamide;
(S)--N-(1-(3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-y-
l)-4,5,6,7-tetrahydro-2H-indazole-3-carboxamide;
(S)--N-(1-(3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-y-
l)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-2-carboxamide;
(S)--N-(1-(3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-y-
l)-2,4,6,7-tetrahydropyrano[4,3-c]pyrazole-3-carboxamide;
(S)--N-(1-(3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-y-
l)-1-(6-methylpyridin-2-yl)-1H-imidazole-4-carboxamide;
(S)--N-(1-(3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-y-
l)-6,7-dihydro-4H-pyrano[3,4-d]isoxazole-3-carboxamide; or
(S)--N-(1-(3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-y-
l)-5-(2-hydroxypropan-2-yl)isoxazole-3-carboxamide.
2. The compound according to claim 1, wherein the compound is of
formula (I), wherein R.sub.x is halogen; R.sub.14 is C.sub.1-7
alkyl; and ring A is chosen from groups (1), (2), (3), (5), (6),
(7) and (8).
3. The compound according to claim 2, wherein R.sub.x is chloro,
R.sub.14 is methyl, and ring A is any of groups (1), (2), (5), (6)
or (7), R.sub.1 is hydroxy C.sub.3-7 alkyl, imidazolyl or carboxy
C.sub.1-7 alkyl carbonyloxy C.sub.1-7 alkyl; R.sub.2 is C.sub.1-7
alkyl, C.sub.2-7 alkenyl or methylpyrazolyl; R.sub.5 is C.sub.1-7
alkyl, C.sub.3-7 cycloalkyl, hydroxy C.sub.1-7 alkyl or
methylpyrazolyl; R.sub.6 is C.sub.1-7 alkyl, cyano C.sub.1-7 alkyl
or hydroxy C.sub.1-7 alkyl; and R.sub.8 is C.sub.1-7 alkyl,
halogen, oxo C.sub.1-7 alkyl or hydroxy C.sub.1-7 alkyl.
4. The compound according to claim 1, wherein the compound is of
formula (II) wherein R.sub.14 is C.sub.1-7 alkyl; R.sub.14',
R.sub.15 and R.sub.15' is hydrogen; ring B is chosen from groups
(1'), (2'), (3'), (4'), (8'), (16'), (17'), (21'), (23'), (24'),
(25'), (26'), (29'), (39'), (40'), (42') and (43'); R.sub.9 is
hydrogen, halogen, cyano, oxo, C.sub.1-7 alkyl, C.sub.2-7 alkenyl,
C.sub.3-7 cycloalkyl, halo C.sub.1-7 alkyl, cyano C.sub.1-7 alkyl,
hydroxy C.sub.1-7 alkyl, oxo C.sub.1-7 alkyl,
--NH--SO.sub.2--R.sub.19 or an optionally substituted 5-12 membered
heterocyclic ring, wherein each R.sub.9 group is linked to B-ring
via a bond or via a C.sub.1-7 alkylene linker; R.sub.10 is
hydrogen, C.sub.1-7 alkyl or C.sub.3-7 cycloalkyl; and R.sub.19 is
C.sub.1-7 alkyl.
5. The compound according to claim 4, wherein the 5-12 membered
heterocyclic ring is pyrazole, pyridine, isoxazole or imidazole
ring, wherein the 5-12 membered heterocyclic ring is attached to
B-ring via a bond or via C.sub.1-7 alkylene linker.
6. The compound according to claim 5, wherein the 5-12 membered
heterocyclic ring contains comprises 1-3 substituents chosen from
C.sub.1-7 alkyl, C.sub.3-7 cycloalkyl, halogen and hydroxy
C.sub.1-7 alkyl.
7. The compound according to claim 4, wherein R.sub.z is hydrogen
or fluoro, R.sub.14 is methyl; R.sub.14', R.sub.15 and R.sub.15' is
hydrogen; ring B is any of groups (1'), (2'), (4'), (17'), (21') or
(25'); R.sub.9 is hydrogen, halogen, cyano, oxo, C.sub.1-7 alkyl,
C.sub.2-7 alkenyl, C.sub.3-7 cycloalkyl, halo C.sub.1-7 alkyl,
hydroxy C.sub.1-3 alkyl, cyano C.sub.1-7 alkyl, pyrazolyl,
N-methylpyrazolyl, pyridinyl, isoxazolyl, imidazolyl or imidazolyl
methyl; and R.sub.10 is hydrogen, C.sub.1-7 alkyl or C.sub.3-7
cycloalkyl.
8. The compound according to claim 1, wherein the compound is
(S)--N-(1-(3-(3-Chloro-4-cyano-2,5-difluorophenyl)-1H-pyrazol-1-yl)propan-
-2-yl)-2-methyl-1H-imidazole-5-carboxamide;
(S)--N-(1-(3-(3-Chloro-4-cyano-2,5-difluorophenyl)-1H-pyrazol-1-yl)-propa-
n-2-yl)-2-(2-hydroxypropan-2-yl)oxazole-5-carboxamide;
(S)--N-(1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-y-
l)-6-cyanoimidazo[1,2-a]pyridine-2-carboxamide;
(S)--N-(1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-y-
l)-7-oxo-5,6,7,8-tetrahydroimidazo[1,2-a]pyrimidine-2-carboxamide;
(S)--N-(1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-y-
l)-3-isopropyl-1,2,4-oxadiazole-5-carboxamide;
(S)--N-(1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-y-
l)-5,7-dimethylimidazo[1,2-c]pyrimidine-2-carboxamide;
(S)-5-((1H-Imidazol-1-yl)methyl)-N-(1-(3-(3-chloro-4-cyano-5-fluorophenyl-
)-1H-pyrazol-1-yl)propan-2-yl)isoxazole-3-carboxamide;
(S)--N-(1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-y-
l)-5-oxo-5,6-dihydroimidazo[1,2-c]pyrimidine-2-carboxamide;
(S)--N-(1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-y-
l)-1,6-dihydropyrrolo[2,3-c]pyrazole-5-carboxamide;
(S)--N-(1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-y-
l)imidazo[2,1-b]thiazole-6-carboxamide;
(S)--N-(1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-y-
l)-6-nitroimidazo[1,2-a]pyridine-2-carboxamide;
(S)--N-(1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-y-
l)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxamide;
(S)--N-(1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)-propan-2--
yl)-1-isopropyl-2-methyl-1H-imidazole-4-carboxamide;
(S)--N-(1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-y-
l)-5-(2-hydroxypropan-2-yl)-1H-pyrazole-3-carboxamide;
(S)--N-(1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)-propan-2--
yl)-1-(2,2-difluoroethyl)-2-methyl-1H-imidazole-4-carboxamide;
N--((S)-1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)-propan-2--
yl)-1-((R)-2-hydroxypropyl)-2-methyl-1H-imidazole-4-carboxamide;
(S)--N-(1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-y-
l)-1'-methyl-1'1H-1,4'-bipyrazole-3-carboxamide;
(S)--N-(1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-y-
l)-1H,2'H-3,3'-bipyrazole-5-carboxamide;
N--((S)-1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)-propan-2--
yl)-1-((S)-2-hydroxypropyl)-2-methyl-1H-imidazole-4-carboxamide;
(S)--N-(1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-y-
l)-3,3'-bipyridine-6-carboxamide;
(S)--N-(1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)-propan-2--
yl)-6-(3,3-dimethylureido)imidazo[1,2-a]pyridine-2-carboxamide;
(S)--N-(1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)-propan-2--
yl)-6-(methylsulfonamido)imidazo[1,2-a]pyridine-2-carboxamide;
N--((S)-1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-y-
l)-5-(1-hydroxy-2-methylpropyl)isoxazole-3-carboxamide;
(S)--N-(1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-y-
l)-5-(1,5-dimethyl-1H-pyrazol-3-yl)-1,2,4-oxadiazole-3-carboxamide;
(S)--N-(1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-y-
l)-5-(isoxazol-3-yl)-1,2,4-oxadiazole-3-carboxamide;
(S)--N-(1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)-propan-2--
yl)-3-(1H-imidazol-4-yl)-1H-pyrazole-5-carboxamide;
(S)--N-(1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-y-
l)-2-(chloropropan-2-yl)oxazole-4-carboxamide;
(S)--N-(1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)-propan-2--
yl)-2-(2-propen-2-yl)oxazole-4-carboxamide;
(S)--N-(1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-y-
l)-N-5-cyclopropylisoxazole-3,5-dicarboxamide;
(S)-2-Bromo-N-(1-(3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)pro-
pan-2-yl)-1H-imidazole-4-carboxamide;
(S)--N-(1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-y-
l)-1-(2-methylprop-1-enyl)-1H-pyrazole-3-carboxamide;
(S)--N-(1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-y-
l)-1-cyclopropyl-1H-pyrazole-3-carboxamide;
N--((S)-1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-y-
l)-2-(1-hydroxyethyl)-1H-imidazole-4-carboxamide;
(S)-2-acetyl-N-(1-(3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)pr-
opan-2-yl)-1H-imidazole-4-carboxamide;
(S)--N-(1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-y-
l)-2-(2-hydroxypropan-2-yl)-1H-imidazole-4-carboxamide;
(S)--N-(1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)-propan-2--
yl)-2-cyclopropyl-1-methyl-1H-imidazole-4-carboxamide;
(S)--N.sup.4-(1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)prop-
an-2-yl)-1H-imidazole-2,4-dicarboxamide:
4-(1-(3-((S)-1-(3-(3-Chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl-ca-
rbamoyl)-1H-pyrazol-5-yl)ethoxy)-4-oxobutanoic acid;
(S)-5-Chloro-N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)-propan-2-y-
l)-pyrazine-2-carboxamide;
N--((S)-1-(3-(3-Chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-1-((S)-
-2-hydroxypropyl)-2-methyl-1H-imidazole-4-carboxamide;
(S)-1-Butyl-N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-
-2-methyl-1H-imidazole-4-carboxamide;
(S)--N-(1-(3-(3-Chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-5-(2-h-
ydroxypropan-2-yl)-1H-pyrazole-3-carboxamide;
(S)--N-(1-(3-(3-Chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-1'-met-
hyl-1'1H-1,4'-bipyrazole-3-carboxamide;
N--((S)-1-(3-(3-Chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-1-((R)-
-2-hydroxypropyl)-2-methyl-1H-imidazole-4-carboxamide;
(S)-2-Bromo-N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)-propan-2-yl-
)-1H-imidazole-4-carboxamide;
N--((S)-1-(3-(3-Chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-5-(1-h-
ydroxy-2-methylpropyl)isoxazole-3-carboxamide;
(S)--N-(1-(3-(3-Chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-1-(2-c-
yanoethyl)-2-methyl-1H-imidazole-4-carboxamide;
N--((S)-1-(3-(3-Chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-1-(1-c-
yanoethyl)-2-methyl-1H-imidazole-4-carboxamide;
(S)--N-(1-(3-(3-Chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-1-(2-m-
ethylprop-1-enyl)-1H-pyrazole-3-carboxamide;
(S)--N-(1-(3-(3-Chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-3-(1H--
imidazol-4-yl)-1H-pyrazole-5-carboxamide;
(S)--N-(1-(3-(3-Chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-1-cycl-
opropyl-1H-pyrazole-3-carboxamide;
(S)--N-(1-(3-(3-Chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-1-(6-(-
dimethylamino)pyridin-3-yl)-1H-pyrazole-3-carboxamide;
(S)--N-(1-(3-(3-Chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-4,5,6,-
7-tetrahydropyrazolo[1,5-a]pyridine-2-carboxamide);
N--((S)-1-(3-(3-Chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-2-(1-h-
ydroxyethyl)-1H-imidazole-4-carboxamide;
(S)--N-(1-(3-(3-Chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-2-isop-
ropyl-1H-imidazole-4-carboxamide;
(S)-2-Butyl-N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-
-1-methyl-1H-imidazole-4-carboxamide;
(S)--N-(1-(3-(3-Chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-2-(2-h-
ydroxypropan-2-yl)-1-methyl-1H-imidazole-4-carboxamide;
(S)--N-(1-(3-(3-Chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-1-meth-
yl-2-(1-methyl-1H-pyrazol-4-yl)-1H-imidazole-4-carboxamide;
(S)--N-(1-(3-(3-Chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-2-cycl-
opropyl-1-methyl-1H-imidazole-4-carboxamide;
(S)--N.sup.4-(1-(3-(3-Chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)--
1H-imidazole-2,4-dicarboxamide;
(S)--N-(1-(3-(4-Cyano-3-(trifluoromethyl)phenyl)-1H-pyrazol-1-yl)propan-2-
-yl)-2-(2-hydroxypropan-2-yl)oxazole-4-carboxamide or a
pharmaceutically acceptable salt thereof.
9. The compound according to claim 1, wherein the compound is
(S)--N-(2-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propyl)-2--
(2-hydroxypropan-2-yl)oxazole-4-carboxamide;
(R)--N-(2-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propyl)-2--
(2-hydroxypropan-2-yl)oxazole-4-carboxamide;
(R)--N-(2-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propyl)-2--
(2-hydroxypropan-2-yl)-1H-imidazole-4-carboxamide;
(S)--N-(1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-y-
l)-2-(2,2,2-trifluoroethyl)-1H-imidazole-4-carboxamide;
(S)--N-(1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-y-
l)-2-(trifluoromethyl)-1H-imidazole-4-carboxamide;
N--((S)-1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-y-
l)-3-((S)-1-hydroxyethyl)-1,2,4-oxadiazole-5-carboxamide;
N--((S)-1-(3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-y-
l)-3-((R)-1-hydroxyethyl)-1,2,4-oxadiazole-5-carboxamide;
(S)--N-(2-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propyl)-3--
(2-hydroxypropan-2-yl)-1,2,4-oxadiazole-5-carboxamide;
(S)--N-(1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-y-
l)-3-(2-hydroxypropan-2-yl)-1,2,4-oxadiazole-5-carboxamide;
(S)--N-(1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-y-
l)-2-cyclopropyl-1H-imidazole-4-carboxamide;
(S)--N.sup.4-(1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)prop-
an-2-yl)-N.sup.2,N.sup.2-dimethyl-1H-imidazole-2,4-dicarboxamide;
(S)--N-(1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-y-
l)-2-(2-ethoxypropan-2-yl)-1H-imidazole-4-carboxamide;
N--((S)-1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-y-
l)-2-(1-ethoxyethyl)-1H-imidazole-4-carboxamide;
(S)--N-(1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-y-
l)-2-(2-ethoxypropan-2-yl)oxazole-4-carboxamide;
(S)--N-(1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-y-
l)-5-(2-hydroxy-2-methyl propyl)-1H-pyrazole-3-carboxamide; or a
pharmaceutically acceptable salt thereof.
10. A pharmaceutical composition comprising a compound of claim 1
and a pharmaceutically acceptable carrier.
11. A method for the treatment of an androgen receptor dependent
cancer, comprising administering to a subject in need thereof a
therapeutically effective amount of a compound according to claim
1.
12. The method according to claim 11, wherein the androgen receptor
dependent cancer is prostate cancer.
Description
This is a national stage application under .sctn.371 of
International Application No. PCT/FI2012/000022, filed on Apr. 20,
2012, which claims the benefit of priority of Indian Patent
Application No. 570/KOL/2011, filed Apr. 21, 2011.
TECHNICAL FIELD
The present invention relates to therapeutically active compounds
and pharmaceutically acceptable salts and esters thereof useful in
the treatment of nuclear receptor, especially steroid receptor, and
in particular androgen receptor (AR) dependent conditions and
diseases, and to pharmaceutical compositions containing such
compounds. In particular, the invention discloses non-steroidal
carboxamide and structured compounds having utility as
tissue-selective androgen receptor modulators (SARM). The compounds
of the invention, which possess AR antagonist activity, are useful
for treating patients requiring androgen receptor antagonist
therapy. In particular, AR antagonists of the invention are useful
in the treatment or prevention of cancer, particularly AR dependent
cancer such as prostate cancer, and other diseases where AR
antagonism is desired.
BACKGROUND OF THE INVENTION
In recent years, there has been growing interest in the development
of nonsteroidal modulators for steroid receptors for therapeutical
use. It has been shown that nonsteroidal ligands can achieve better
receptor selectivity and better physicochemical, pharmacokinetic
and pharmacological properties. For androgen receptor (AR),
nonsteroidal antagonists (antiandrogens) are now used clinically to
counteract the undesirable actions of excessive androgens.
Androgens, functioning through the AR, are essential for the
initiation and progression of prostate cancer. Thus, treatment of
advanced prostate cancer involves androgen-ablation therapies, such
as surgical castration or hormonal manipulation using
gonadotropin-releasing hormone (GnRH) agonists, anti-androgens or
both. Although such therapies initially lead to disease regression,
eventually all patients progress to a castration resistant late
stage that is refractory to current therapies. Castration-resistant
prostate cancer (CRPC) is associated with increased levels of AR.
First generation anti-androgens such as bicalutamide display
agonistic properties in cells engineered to express higher AR
levels. In vitro and in vivo, increased AR expression has been
shown to confer resistance of prostate cancer cell lines to
anti-androgen therapy. To overcome resistance problems, second
generation anti-androgens that retain antagonism in cells
expressing excess AR may have utility in the treatment of CRPC.
Non-steroidal androgen receptor antagonists have been described
earlier e.g. in patent publications EP 100172, EP 1790640, U.S.
Pat. No. 6,087,509, U.S. Pat. No. 6,673,799, U.S. Pat. No.
7,271,188, WO 03/057669, WO 2004/099188, WO 2006/133567, WO
2008/124000, WO 2009/028543 and WO 2009/055053.
Related carboxamide structured compounds have been described in WO
2008/062878.
SUMMARY OF THE INVENTION
It has been found that compounds of formula (I) or (II) are potent
androgen receptor (AR) modulators, in particular AR antagonists.
Compounds of formula (I) or (II) show remarkably high affinity and
strong antagonistic activity in androgen receptor. Also in cells
which overexpress AR ("AR overexpressing cells") the compounds of
the invention possess from high to full AR antagonism while
exhibiting only minimal agonism. The compounds of the invention
also effectively inhibited proliferation of prostatic cancer cell
line. Moreover, the compounds of the invention have low potential
for drug-drug interactions, high selectivity to androgen receptor,
favourable safety profile and sufficient water solubility.
The compounds of the invention are therefore particularly useful as
medicaments in the treatment of prostate cancer and other AR
dependent conditions and diseases where AR antagonism is
desired.
The present invention provides novel carboxamide structured
compounds of formula (I) or (II)
##STR00002##
wherein ring A is any one of the following groups or tautomers
thereof
##STR00003##
wherein
R.sub.X is halogen or CF.sub.3;
R.sub.Z is hydrogen or halogen;
R.sub.1 is hydroxy C.sub.3-7 alkyl, imidazolyl or
--R.sub.A--OC(O)--R.sub.B;
R.sub.A is C.sub.1-7 alkyl;
R.sub.B is C.sub.1-7 alkyl, hydroxy C.sub.1-7 alkyl or carboxy
C.sub.1-7 alkyl;
R.sub.2 is C.sub.1-7 alkyl, C.sub.2-7 alkenyl, C.sub.3-7
cycloalkyl, C.sub.3-7 cycloalkyl C.sub.1-7 alkyl, methylpyrazolyl
or pyrimidinyl;
R.sub.3 is halogen or pyridinyl;
R.sub.4 is pyridinyl;
R.sub.5 is C.sub.1-7 alkyl, C.sub.2-7 alkenyl, C.sub.3-7
cycloalkyl, C.sub.3-7 cycloalkyl C.sub.1-7 alkyl, cyano, hydroxy
C.sub.1-7 alkyl, oxo C.sub.1-7 alkyl, halogen or
methylpyrazolyl;
R.sub.6 is C.sub.1-7 alkyl, C.sub.2-7 alkenyl, C.sub.3-7
cycloalkyl, C.sub.3-7 cycloalkyl C.sub.1-7 alkyl, hydroxy, hydroxy
C.sub.1-7 alkyl, cyano C.sub.1-7 alkyl or C.sub.1-7 alkoxycarbamoyl
C.sub.1-7 alkyl;
R.sub.7 is hydroxy C.sub.4 alkyl;
R.sub.8 is halogen, C.sub.2-7 alkyl, C.sub.2-7 alkenyl, C.sub.3-7
cycloalkyl, C.sub.3-7 cycloalkyl C.sub.1-7 alkyl, cyano, carboxy,
oxo C.sub.1-7 alkyl, halo C.sub.1-7 alkyl, hydroxy C.sub.1-7 alkyl,
tetrahydro-2H-thiopyran or --C(O)--NHR.sub.20;
R.sub.9 is hydrogen, hydroxy, halogen, nitro, amino, cyano, oxo,
C.sub.1-7 alkyl, C.sub.2-7 alkenyl, C.sub.3-7 cycloalkyl, C.sub.1-7
alkoxy, halo C.sub.1-7 alkyl, hydroxy C.sub.1-7 alkyl, cyano
C.sub.1-7 alkyl, amino C.sub.1-7 alkyl, oxo C.sub.1-7 alkyl,
C.sub.1-7 alkoxy C.sub.1-7 alkyl, C.sub.1-7 alkylamino, hydroxy
C.sub.1-7 alkylamino, C.sub.1-7 alkoxy C.sub.1-7 alkylamino,
C.sub.1-7 alkylamino C.sub.1-7 alkyl, hydroxy C.sub.1-7 alkylamino
C.sub.1-7 alkyl, hydroxyimino C.sub.1-7 alkyl, C.sub.1-7
alkoxycarbamoyl C.sub.1-7 alkyl, --C(O)R.sub.11, --OC(O)R.sub.17,
--NH--C(O)R.sub.18--NH--SO.sub.2--R.sub.19 or an optionally
substituted 5-12 membered carbocyclic or heterocyclic ring, each
group linked to B-ring via a bond or via a C.sub.1-7 alkylene
linker;
R.sub.10 is hydrogen, halogen, C.sub.1-7 alkyl, C.sub.2-7 alkenyl,
C.sub.3-7 cycloalkyl, C.sub.3-7 cycloalkyl C.sub.1-7 alkyl, oxo,
hydroxy C.sub.1-7 alkyl, oxo C.sub.1-7 alkyl or an optionally
substituted 5 or 6 membered carbocyclic or heterocyclic ring;
R.sub.11 is hydrogen, hydroxy, C.sub.1-7 alkyl, hydroxy C.sub.1-7
alkyl, C.sub.2-7 alkenyl, C.sub.3-7 cycloalkyl, halo C.sub.1-7
alkyl, C.sub.1-7 alkoxy, NR.sub.12R.sub.13, or an optionally
substituted 5-12 membered carbocyclic or heterocyclic ring;
R.sub.12 is hydrogen, C.sub.1-7 alkyl, C.sub.2-7 alkenyl, C.sub.3-7
cycloalkyl, C.sub.3-7 cycloalkyl C.sub.1-7 alkyl, C.sub.1-7 alkoxy,
hydroxy C.sub.1-7 alkyl, amino C.sub.1-7 alkyl or C.sub.1-7 alkyl
amino C.sub.1-7 alkyl;
R.sub.13 is hydrogen or C.sub.1-7 alkyl;
R.sub.14 and R.sub.15 are, independently, hydrogen or C.sub.1-7
alkyl;
R.sub.14' and R.sub.15' are, independently, hydrogen or C.sub.1-7
alkyl, or R.sub.14' and R.sub.15' together form a bond;
R.sub.17 is C.sub.1-7 alkyl, C.sub.2-7 alkenyl, C.sub.3-7
cycloalkyl, C.sub.3-7 cycloalkyl C.sub.1-7 alkyl, C.sub.1-7 alkoxy,
amino C.sub.1-7 alkyl, C.sub.1-7 alkylamino or C.sub.1-7 alkylamino
C.sub.1-7 alkyl;
R.sub.18 is C.sub.1-7 alkyl, C.sub.2-7 alkenyl, C.sub.3-7
cycloalkyl, C.sub.3-7 cycloalkyl C.sub.1-7 alkyl, amino C.sub.1-7
alkyl, C.sub.1-7 alkylamino or C.sub.1-7 alkylamino C.sub.1-7
alkyl;
R.sub.19 is C.sub.1-7 alkyl, C.sub.2-7 alkenyl, C.sub.3-7
cycloalkyl or C.sub.3-7 cycloalkyl C.sub.1-7 alkyl;
R.sub.20 is hydrogen, C.sub.1-7 alkyl, C.sub.2-7 alkenyl, C.sub.3-7
cycloalkyl, C.sub.3-7 cycloalkyl C.sub.1-7 alkyl or C.sub.1-7
alkoxy;
R.sub.21 is cyano C.sub.1-7 alkyl or, in case R.sub.X is CF.sub.3,
R.sub.21 can also be hydroxy C.sub.1-7 alkyl;
R.sub.22 is hydroxy C.sub.1-7 alkyl;
R.sub.23 is C.sub.1-7 alkyl or hydroxy C.sub.1-7 alkyl;
R.sub.24 is hydroxy, halogen or C.sub.1-7 alkoxy; ring B is any one
of the following groups or tautomers thereof
##STR00004## ##STR00005## ##STR00006## ##STR00007##
and pharmaceutically acceptable salts thereof;
with the proviso that the compound of formula (II) is not any of
the following compounds:
(S)-3-acetyl-N-(1-(3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)-p-
ropan-2-yl)-1H-pyrazole-5-carboxamide;
(S)--N-(1-(3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-y-
l)-1-(pyridin-4-yl)-1H-pyrazole-3-carboxamide;
(S)--N-(1-(3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-y-
l)-1-(2-fluoroethyl)-2-methyl-1H-imidazole-4-carboxamide;
(S)--N-(1-(3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-y-
l)-3-(1H-imidazol-4-yl)-1,2,4-oxadiazole-5-carboxamide;
(S)-5-acetyl-N-(1-(3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)pr-
opan-2-yl)isoxazole-3-carboxamide;
N--((S)-1-(3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-y-
l)-5-(1-hydroxyethyl)isoxazole-3-carboxamide;
(S)-5-acetyl-N-(2-(3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)pr-
opyl)isoxazole-3-carboxamide;
(S)--N-(2-(3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propyl)-2--
methyl-1H-imidazole-4-carboxamide;
N--((S)-1-(3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-y-
l)-3-(1-hydroxyethyl)-1H-pyrazole-5-carboxamide;
(R)--N-(1-(3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-y-
l)-2-methyl-1H-imidazole-4-carboxamide;
(S)--N-{1-[3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl]propan-2-y-
l}-2-methyl-1H-imidazole-4-carboxamide;
(S)--N-{1-[3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl]propan-2-y-
l}-1-methyl-1H-imidazole-4-carboxamide;
(S)--N-(1-(3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-y-
l)-3H-imidazo[4,5-b]pyridine-5-carboxamide;
(S)--N-(1-(3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-y-
l)-2-(pyridin-3-yl)thiazole-4-carboxamide;
(S)--N-(1-(3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-y-
l)-1-(pyridin-3-yl)-1H-pyrazole-3-carboxamide;
(S)--N-(1-(3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-y-
l)-2-methyl-1-(3-oxobutyl)-1H-imidazole-4-carboxamide;
(S)--N-(1-(3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-y-
l)-1-(3-hydroxy-3-methylbutyl)-2-methyl-1H-imidazole-4-carboxamide;
(S)--N-(1-(3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-y-
l)imidazo[1,2-a]pyridine-2-carboxamide;
(S)--N-(1-(3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-y-
l)-1-(pyridin-3-yl)-1H-imidazole-4-carboxamide;
(S)--N-(1-(3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-y-
l)-2-(2-hydroxypropan-2-yl)oxazole-4-carboxamide;
(S)--N-(1-(3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-y-
l)imidazo[1,2-a]pyrimidine-2-carboxamide;
(S)--N-(1-(3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-y-
l)-3-fluoroimidazo pyridine-2-carboxamide;
(S)--N-(1-(3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-y-
l)-4,5,6,7-tetrahydro-2H-indazole-3-carboxamide;
(S)--N-(1-(3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-y-
l)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-2-carboxamide;
(S)--N-(1-(3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-y-
l)-2,4,6,7-tetrahydropyrano[4,3-c]pyrazole-3-carboxamide;
(S)--N-(1-(3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-y-
l)-1-(6-methylpyridin-2-yl)-1H-imidazole-4-carboxamide;
(S)--N-(1-(3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-y-
l)-6,7-dihydro-4H-pyrano[3,4-d]isoxazole-3-carboxamide;
(S)--N-(1-(3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-y-
l)-5-(2-hydroxypropan-2-yl)isoxazole-3-carboxamide.
It is to be understood that each B-ring (1') to (45') above are
substituted by R.sub.9 and R.sub.10 as shown in formula (II).
In a subclass of compounds of formula (I) or (II) are compounds of
formula (I') or (II') and pharmaceutically acceptable salts
thereof, wherein R.sub.x, R.sub.z, R.sub.9, R.sub.10, A and B are
as defined above.
##STR00008##
In a subclass of preferred compounds of formula (I) or (I') are
compounds and pharmaceutically acceptable salts thereof wherein
R.sub.x is halogen, R.sub.14 is C.sub.1-7 alkyl, and ring A is any
of groups (1), (2), (3), (5), (6), (7) or (8). A further subclass
of preferred compounds formula (I) or (I') are compounds and
pharmaceutically acceptable salts thereof wherein R.sub.x is
chloro, R.sub.14 is methyl, and ring A is any of groups (1), (2),
(5), (6) or (7), R.sub.1 is hydroxy C.sub.3-7 alkyl, imidazolyl or
carboxy C.sub.1-7 alkyl carbonyloxy C.sub.1-7 alkyl, R.sub.2 is
C.sub.1-7 alkyl, C.sub.2-7 alkenyl or methylpyrazolyl, R.sub.5 is
C.sub.1-7 alkyl, C.sub.3-7 cycloalkyl, hydroxy C.sub.1-7 alkyl or
methylpyrazolyl, R.sub.6 is C.sub.1-7 alkyl, cyano C.sub.1-7 alkyl
or hydroxy C.sub.1-7 alkyl and R.sub.8 is C.sub.1-7 alkyl, halogen,
oxo C.sub.1-7 alkyl or hydroxy C.sub.1-7 alkyl.
In a subclass of preferred compounds of formula (II) or (II') are
compounds and pharmaceutically acceptable salts thereof wherein
R.sub.14 is C.sub.1-7 alkyl, R.sub.14', R.sub.15 and R.sub.15' is
hydrogen, ring B is any of groups (1'), (2'), (3'), (4'), (8'),
(16'), (17'), (21'), (23'), (24'), (25'), (26'), (29'), (39'),
(40'), (42') or (43'), R.sub.9 is hydrogen, halogen, cyano, oxo,
C.sub.1-7 alkyl, C.sub.2-7 alkenyl, C.sub.3-7 cycloalkyl, halo
C.sub.1-7 alkyl, cyano C.sub.1-7 alkyl, hydroxy C.sub.1-7 alkyl,
oxo C.sub.1-7 alkyl, --NH--SO.sub.2--R.sub.19 or an optionally
substituted 5-12 membered heterocyclic ring, each R.sub.9 group
linked to B-ring via a bond or via a C.sub.1-7 alkylene linker,
R.sub.10 is hydrogen, C.sub.1-7 alkyl or C.sub.3-7 cycloalkyl, and
R.sub.19 is C.sub.1-7 alkyl. Particularly preferred 5-12 membered
heterocyclic ring in R.sub.9 is pyrazole, pyridine, isoxazole or
imidazole ring, which is attached to B-ring via a bond or via
C.sub.1-7 alkylene linker. Particularly preferred substituents in
the 5-12 membered heterocyclic ring in R.sub.9 are 1 to 3
substituents selected from C.sub.1-7 alkyl, C.sub.3-7 cycloalkyl,
halogen or hydroxy C.sub.1-7 alkyl groups.
Still another class of preferred compounds are compounds of formula
(II) or (II') and pharmaceutically acceptable salts thereof wherein
R.sub.z is hydrogen or fluoro, R.sub.14 is methyl, R.sub.14',
R.sub.15 and R.sub.15' is hydrogen, ring B is any of groups (1'),
(2'), (4'), (17'), (21') or (25'), R.sub.9 is hydrogen, halogen,
cyano, oxo, C.sub.1-7 alkyl, C.sub.2-7 alkenyl, C.sub.3-7
cycloalkyl, halo C.sub.1-7 alkyl, hydroxy C.sub.1-3 alkyl, cyano
C.sub.1-7 alkyl, pyrazolyl, N-methyl pyrazolyl, pyridinyl,
isoxazolyl, imidazolyl or imidazolyl methyl, and R.sub.10 is
hydrogen, C.sub.1-7 alkyl or C.sub.3-7 cycloalkyl.
The present invention provides further a method for the treatment
or prevention of androgen receptor (AR) dependent conditions,
comprising administering to a subject in need thereof a
therapeutically effective amount of a compound of formula (I) or
(II) or pharmaceutically acceptable salts thereof. For example, the
AR dependent condition to be treated is cancer, particularly AR
dependent cancer such as prostate cancer, benign prostatic
hyperplasia, androgenic alopecia and acne. According to one
embodiment of the invention, the AR dependent condition to be
treated is castration-resistant prostate cancer (CRPC).
The present invention also provides a pharmaceutical composition
comprising a compound of formula (I) or (II) or pharmaceutically
acceptable salts thereof together with a pharmaceutically
acceptable carrier.
DETAILED DESCRIPTION OF THE INVENTION
The compounds of the invention can be prepared by a variety of
synthetic routes analogously to the methods known in the literature
using suitable starting materials. For example, compounds of
formula (I) or (II) can be prepared according to the reaction
Scheme 1, wherein R.sub.z, R.sub.14, R.sub.14', R.sub.15,
R.sub.15', B, R.sub.9, and R.sub.10 are as defined above and X is a
halogen. Preparation of compounds of formula (II) is shown in
Schemes 1 and 2, but compounds of formula (I) can be prepared in
analogous manner following the methods of Schemes 1 and 2.
Optically active enantiomers or diastereomers of compounds of
formula (I) or (II) can be prepared e.g. by using suitable
optically active starting materials. Similarly, racemic compounds
of formula (I) or (II) can be prepared by using racemic starting
materials. Some compounds included in the formula (I) or (II) can
be obtained by converting the functional groups of the other
compounds of formula (I) or (II) obtained in accordance with Scheme
1, by well known reaction steps such as oxidation, reduction,
hydrolysis, acylation, alkylation, amidation, amination and
others.
##STR00009##
Alternatively, compounds of formula (I) or (II) can be prepared
according to the Scheme 2. R.sub.z, R.sub.14, R.sub.14', R.sub.15,
R.sub.15', B, R.sub.9, and R.sub.10 are as defined above and X is a
halogen.
##STR00010##
The starting compound [11] of Scheme 2 can be suitably prepared
from 3-chloro-5-fluoroaniline according to Scheme 3, wherein X is a
halogen.
##STR00011##
Other starting materials of the above Schemes are commercially
available or can be prepared according to known methods.
Pharmaceutically acceptable salts, e.g. acid addition salts with
both organic and inorganic acids are well known in the field of
pharmaceuticals. Non-limiting examples of these salts include
chlorides, bromides, sulfates, nitrates, phosphates, sulfonates,
formates, tartrates, maleates, citrates, benzoates, salicylates and
ascorbates. Pharmaceutically acceptable esters, when applicable,
may be prepared by known methods using pharmaceutically acceptable
acids that are conventional in the field of pharmaceuticals and
that retain the pharmacological properties of the free form.
Non-limiting examples of these esters include esters of aliphatic
or aromatic alcohols, e.g. methyl, ethyl, propyl, isopropyl, butyl,
isobutyl, sec-butyl, tert-butyl esters. Phosphate esters and
carbonate esters, are also within the scope of the invention.
The definition of formula (I) or (II) above are inclusive of all
the possible isotopes and stereoisomers of the compounds, including
geometric isomers, e.g. Z and E isomers (cis and trans isomers),
and optical isomers, e.g. diastereomers and enantiomers, and all
prodrug esters, e.g. phosphate esters and carbonate esters.
Furthermore, the invention includes in its scope both the
individual isomers and any mixtures thereof, e.g. racemic
mixtures.
In one embodiment, the term "isomer" is meant to encompass optical
isomers of the compounds of the invention. It will be appreciated
by those skilled in the art that the compounds of the present
invention contain at least one chiral center. Accordingly, the
compounds of the invention may exist in optically active or racemic
forms. It is to be understood that the present invention
encompasses any racemic or optically active form, or mixtures
thereof. In one embodiment, the compounds of the invention are the
pure (R)-isomers. In another embodiment, the compounds of the
invention are the pure (S)-isomers. In another embodiment, the
compounds of the invention are a mixture of the (R) and the (S)
isomers. In another embodiment, the compounds of the invention are
a racemic mixture comprising an equal amount of the (R) and the (S)
isomers. The compounds of the invention may contain two chiral
centers. In such case, according to one embodiment of the
invention, the compounds of the invention are pure diasteromers.
According to other embodiment of the invention, the compounds of
the invention are a mixture of several diasteromers. The individual
isomers may be obtained using the corresponding isomeric forms of
the starting material or they may be separated after the
preparation of the end compound according to conventional
separation methods. For the separation of optical isomers, e.g.
enantiomers or diastereomers, from the mixture thereof the
conventional resolution methods, e.g. fractional crystallisation,
may be used.
The terms employed herein have the following meanings:
The term "halo" or "halogen", as employed herein as such or as part
of another group, refers to chlorine, bromine, fluorine or
iodine.
The terms "C.sub.1-7 alkyl", "C.sub.2-7 alkyl" and "C.sub.4 alkyl",
as employed herein as such or as part of another group, refers to a
saturated straight or branched carbon chain having 1 to 7 carbon
atoms, 2 to 7 carbon atoms and 4 carbon atoms, respectively.
Representative examples of C.sub.1-7 alkyl include, but are not
limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,
sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, and
the like.
The term "C.sub.2-7 alkenyl", as employed herein as such or as part
of another group, refers to a straight or branched chain radical
having 2 to 7 carbon atoms, which chain contains at least one
double bond. Representative examples of C.sub.2-7 alkenyl include,
but are not limited to, ethenyl, propenyl, butenyl, and the
like.
The term "C.sub.1-7 alkylene linker" means a saturated straight or
branched C.sub.1-7 alkyl chain which connects two groups together.
Representative examples of C.sub.1-7 alkylene linker are methylene
(--CH.sub.2--) and ethylene (--CH.sub.2--CH.sub.2--) chains.
The term "C.sub.3-7 cycloalkyl", as employed herein as such or as
part of another group, refers to a saturated cyclic hydrocarbon
group containing 3 to 7 carbons. Representative examples of
C.sub.3-7 cycloalkyl include, but are not limited to, cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl, and the like.
The term "C.sub.3-7 cycloalkyl C.sub.1-7 alkyl", as employed herein
refers to a C.sub.3-7 cycloalkyl group, as defined herein, appended
to the parent molecular moiety through a C.sub.1-7 alkyl group, as
defined herein.
The term "hydroxy", as employed herein as such or as part of
another group, refers to an --OH group.
The term "cyano", as employed herein as such or as part of another
group, refers to a --CN group.
The term "hydroxy C.sub.1-7 alkyl", as employed herein as such or
as part of another group, refers to at least one hydroxy group, as
defined herein, appended to the parent molecular moiety through a
C.sub.1-7 alkyl group, as defined herein. Representative examples
of hydroxy C.sub.1-7 alkyl include, but are not limited to,
hydroxymethyl, 2,2-dihydroxyethyl, 1-hydroxyethyl, 3-hydroxypropyl,
1-hydroxypropyl, 1-methyl-1-hydroxyethyl, 1-methyl-1-hydroxypropyl,
and the like.
The term "halo C.sub.1-7 alkyl", as employed herein as such or as
part of another group, refers to at least one halogen, as defined
herein, appended to the parent molecular moiety through a C.sub.1-7
alkyl group, as defined herein. Representative examples of halo
C.sub.1-7 alkyl include, but are not limited to, fluoromethyl,
difluoro-methyl, trifluoromethyl, 2-chloroethyl, 3-bromopropyl, and
the like.
The term "cyano C.sub.1-7 alkyl", as employed herein as such or as
part of another group, refers to at least one cyano group, appended
to the parent molecular moiety through a C.sub.1-7 alkyl group, as
defined herein. Representative examples include, but are not
limited to, cyanomethyl, 3-cyanopropyl, and the like.
The term "C.sub.1-7 alkoxy C.sub.1-7 alkyl", refers to C.sub.1-7
alkoxy group as defined herein, appended to the parent molecular
moiety through a C.sub.1-7 alkyl group, as defined herein.
The term "oxo" as employed herein as such or as part of another
group, refers to group (.dbd.O) attached as a substituent.
The term "carboxyl", as employed herein as such or as part of
another group, refers to a --COOH group.
The term "carbamoyl", as employed herein as such or as part of
another group, refers to a --(C.dbd.O)--NH.sub.2 group.
The term "carbamoyl C.sub.1-7 alkyl", as employed herein as such or
as part of another group, refers to carbamoyl group appended to the
parent molecular moiety through a C.sub.1-7 alkyl group.
The term "carboxy C.sub.1-7 alkyl" employed herein, refers to
--COOH group appended to the parent molecular moiety through a
C.sub.1-7 alkyl group, as defined herein.
The term "C.sub.1-7 alkoxycarbamoyl C.sub.1-7 alkyl" as employed
herein, refers to --C.sub.1-7 alkyl-(C.dbd.O)--NH--O--C.sub.1-7
alkyl group wherein C.sub.1-7 alkyl is as defined herein.
The term "amino", as employed herein as such or as part of another
group, refers to a --NH.sub.2 group.
The term "oxo C.sub.1-7 alkyl", as employed herein by itself or as
part of another group, refers a C.sub.1-7 alkyl group as defined
herein containing a carbonyl radical anywhere in an alkyl chain.
Examples thereof include acetyl, propanoyl, iso-propanoyl,
butanoyl, sec-butanoyl, tert-butanoyl and pentanoyl.
The term "amino C.sub.1-7 alkyl", as employed herein, refers to at
least one amino group, as defined herein, appended to the parent
molecular moiety through a C.sub.1-7 alkyl group, as defined
herein. Representative examples of amino C.sub.1-7 alkyl include,
but are not limited to, aminomethyl, 2-aminoethyl, 1-aminoethyl,
2,2-di-aminoethyl, 3-aminopropyl, 2-aminopropyl, 4-aminobutyl,
1-methyl-1-aminoethyl, and the like.
The term "C.sub.1-7 alkylamino", as employed herein as such or as
part of another group, refers to one or two C.sub.1-7 alkyl
group(s), as defined herein, appended to the parent molecular
moiety through an amino group, as defined herein. Representative
examples of C.sub.1-7 alkylamino include, but are not limited to
methylamino, ethylamino, propylamino, dimethylamino, diethylamino,
N-ethyl-N-methylamino, and the like.
The term "C.sub.1-7 alkylamino C.sub.1-7 alkyl", as employed
herein, refers to C.sub.1-7 alkylamino group, as defined herein,
appended to the parent molecular moiety through a C.sub.1-7 alkyl
group, as defined herein. Representative examples of C.sub.1-7
alkylamino C.sub.1-7 alkyl include, but are not limited to,
N,N-dimethylaminomethyl, N,N-di-ethylaminomethyl,
N-methylaminoethyl, N-methylaminopropyl,
N-ethyl-N-methyl-aminomethyl, and the like.
The term "hydroxy C.sub.1-7 alkylamino", as employed herein, refers
to at least one hydroxy group appended to the parent molecular
moiety through a C.sub.1-7 alkylamino group, as defined herein.
Representative examples of C.sub.1-7 alkylamino C.sub.1-7 alkyl
include, but are not limited to, N-hydroxymethylamino,
N-ethyl-N-hydroxymethylamino, and the like.
The term "C.sub.1-7 alkoxy C.sub.1-7 alkylamino", as employed
herein refers to at least one C.sub.1-7 alkoxy group appended to
the parent molecular moiety through a C.sub.1-7 alkylamino group,
as defined herein. Representative examples include, but are not
limited to, N-ethoxymethylamino, N-ethyl-N-metoxymethylamino and
the like.
The term "hydroxy C.sub.1-7 alkylamino C.sub.1-7 alkyl", as
employed herein, refers to hydroxy C.sub.1-7 alkylamino group, as
defined herein, appended to the parent molecular moiety through a
C.sub.1-7 alkyl group, as defined herein. Representative examples
of C.sub.1-7 alkylamino C.sub.1-7 alkyl include, but are not
limited to, N-hydroxymethylaminoethyl,
N-ethyl-N-hydroxymethylaminomethyl, and the like.
The term "C.sub.1-7 alkoxy C.sub.1-7 alkyl", as employed herein,
refers to at least one C.sub.1-7 alkoxy group, as defined herein,
appended to the parent molecular moiety through a C.sub.1-7 alkyl
group, as defined herein. Representative examples of C.sub.1-7
alkoxy C.sub.1-7 alkyl include, but are not limited to
methoxymethyl, ethoxymethyl, 2-methoxy-ethyl, 2-ethoxyethyl,
3,3-dimethoxypropyl, 2,4-dimethoxybutyl and the like.
The term "imino C.sub.1-7 alkyl", as employed herein, refers to at
least one imino group (.dbd.NH) appended to the parent molecular
moiety through a C.sub.1-7 alkyl group, as defined herein.
The term "hydroxyimino C.sub.1-7 alkyl", as employed herein, refers
to .dbd.N--OH group appended to the parent molecular moiety through
a C.sub.1-7 alkyl group, as defined herein.
The term "5- or 6-membered heterocyclic ring" as employed herein,
refers to a saturated, partially saturated or aromatic ring with 5
or 6 ring atoms, of which 1-3 atoms are heteroatoms selected from a
group consisting of N, O and S. Representative examples of 5- or
6-membered heterocyclic ring include, but are not limited to,
pyrazolyl, pyridinyl, isoxazolyl, imidazolyl, furanyl, piperazinyl,
piperidinyl, rings and the like.
The term "5- or 6-membered carbocyclic ring" as employed herein,
refers to a saturated, partially saturated or aromatic ring with 5
or 6 ring atoms consisting of carbon atoms only. Representative
examples of 5- or 6-membered carbocyclic ring include, but are not
limited to, phenyl and cyclohexyl rings and the like.
The term "5-12 membered heterocyclic ring" as employed herein,
refers to a monocyclic or bicyclic saturated, partially saturated
or aromatic ring with 5 to 12 ring atoms, of which 1-4 atoms are
heteroatoms selected from a group consisting of N, O and S.
Representative examples of 5-12 membered heterocyclic ring include,
but are not limited to, pyrazolyl, pyridinyl, isoxazolyl,
imidazolyl, furanyl, piperazinyl, piperidinyl, morpholinyl,
pyrazinyl, indazolyl, pyrazolo[1,5-a]pyrimidinyl, isoxazolyl and
thiazolyl rings and the like.
The term "5-12 membered carbocyclic ring" as employed herein,
refers to a monocyclic or bicyclic saturated, partially saturated
or aromatic ring with 5 to 12 ring atoms consisting of carbon atoms
only. Representative examples of 5-12 membered carbocyclic rings
include, but are not limited to, phenyl and naphtyl rings and the
like.
The term "optionally substituted" as used herein in connection with
various residues refers to halogen, C.sub.1-7 alkyl, C.sub.2-7
alkenyl, C.sub.3-7 cycloalkyl, hydroxy, amino, halo C.sub.1-7
alkyl, hydroxy C.sub.1-7 alkyl, C.sub.1-7 alkoxy, oxo C.sub.1-7
alkyl, C.sub.1-7 alkylamino, amino C.sub.1-7 alkyl, methylsulfonyl,
nitro, cyano or thiol substituents. Preferred substituents are
halogen, C.sub.1-7 alkyl, C.sub.3-7 cycloalkyl, hydroxy C.sub.1-7
alkyl, oxo C.sub.1-7 alkyl substituents. The "optionally
substituted" groups may contain 1 to 3, preferably 1 or 2, most
preferably 1 of the above mentioned substituents.
Examples of preferred compounds of formula (I) or (II) include
(S)--N-(1-(3-(3-Chloro-4-cyano-2,5-difluorophenyl)-1H-pyrazol-1-yl)propan-
-2-yl)-2-methyl-1H-imidazole-5-carboxamide;
(S)--N-(1-(3-(3-Chloro-4-cyano-2,5-difluorophenyl)-1H-pyrazol-1-yl)-propa-
n-2-yl)-2-(2-hydroxypropan-2-yl)oxazole-5-carboxamide;
(S)--N-(1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-y-
l)-6-cyanoimidazo[1,2-a]pyridine-2-carboxamide;
(S)--N-(1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-y-
l)-7-oxo-5,6,7,8-tetrahydroimidazo[1,2-a]pyrimidine-2-carboxamide;
(S)--N-(1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-y-
l)-3-isopropyl-1,2,4-oxadiazole-5-carboxamide;
(S)--N-(1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-y-
l)-5,7-dimethylimidazo[1,2-c]pyrimidine-2-carboxamide;
(S)-5-((1H-Imidazol-1-yl)methyl)-N-(1-(3-(3-chloro-4-cyano-5-fluorophenyl-
)-1H-pyrazol-1-yl)propan-2-yl)isoxazole-3-carboxamide;
(S)--N-(1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-y-
l)-5-oxo-5,6-dihydroimidazo[1,2-c]pyrimidine-2-carboxamide;
(S)--N-(1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-y-
l)-1,6-dihydropyrrolo[2,3-c]pyrazole-5-carboxamide;
(S)--N-(1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-y-
l)imidazo[2,1-b]thiazole-6-carboxamide;
(S)--N-(1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-y-
l)-6-nitroimidazo[1,2-a]pyridine-2-carboxamide;
(S)--N-(1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-y-
l)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxamide;
(S)--N-(1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)-propan-2--
yl)-1-isopropyl-2-methyl-1H-imidazole-4-carboxamide;
(S)--N-(1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-y-
l)-5-(2-hydroxypropan-2-yl)-1H-pyrazole-3-carboxamide;
(S)--N-(1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)-propan-2--
yl)-1-(2,2-difluoroethyl)-2-methyl-1H-imidazole-4-carboxamide;
N--((S)-1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)-propan-2--
yl)-1-((R)-2-hydroxypropyl)-2-methyl-1H-imidazole-4-carboxamide;
(S)--N-(1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-y-
l)-1'-methyl-1'H-1,4'-bipyrazole-3-carboxamide;
(S)--N-(1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-y-
l)-1H,2'H-3,3'-bipyrazole-5-carboxamide;
N--((S)-1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)-propan-2--
yl)-1-((S)-2-hydroxypropyl)-2-methyl-1H-imidazole-4-carboxamide;
(S)--N-(1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-y-
l)-3,3'-bipyridine-6-carboxamide;
(S)--N-(1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)-propan-2--
yl)-6-(3,3-dimethylureido)imidazo[1,2-a]pyridine-2-carboxamide;
(S)--N-(1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)-propan-2--
yl)-6-(methylsulfonamido)imidazo[1,2-a]pyridine-2-carboxamide;
N--((S)-1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-y-
l)-5-(1-hydroxy-2-methylpropyl)isoxazole-3-carboxamide;
(S)--N-(1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-y-
l)-5-(1,5-dimethyl-1H-pyrazol-3-yl)-1,2,4-oxadiazole-3-carboxamide;
(S)--N-(1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-y-
l)-5-(isoxazol-3-yl)-1,2,4-oxadiazole-3-carboxamide;
(S)--N-(1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)-propan-2--
yl)-3-(1H-imidazol-4-yl)-1H-pyrazole-5-carboxamide;
(S)--N-(1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-y-
l)-2-(chloropropan-2-yl)oxazole-4-carboxamide;
(S)--N-(1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)-propan-2--
yl)-2-(2-propen-2-yl)oxazole-4-carboxamide;
(S)--N-(1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-y-
l)-N-5-cyclopropylisoxazole-3,5-dicarboxamide;
(S)-2-Bromo-N-(1-(3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)-pr-
opan-2-yl)-1H-imidazole-4-carboxamide;
(S)--N-(1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-y-
l)-1-(2-methylprop-1-enyl)-1H-pyrazole-3-carboxamide;
(S)--N-(1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-y-
l)-1-cyclopropyl-1H-pyrazole-3-carboxamide;
N--((S)-1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-y-
l)-2-(1-hydroxyethyl)-1H-imidazole-4-carboxamide;
(S)-2-acetyl-N-(1-(3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)-p-
ropan-2-yl)-1H-imidazole-4-carboxamide;
(S)--N-(1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-y-
l)-2-(2-hydroxypropan-2-yl)-1H-imidazole-4-carboxamide;
(S)--N-(1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)-propan-2--
yl)-2-cyclopropyl-1-methyl-1H-imidazole-4-carboxamide;
(S)--N.sup.4-(1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)prop-
an-2-yl)-1H-imidazole-2,4-dicarboxamide:
4-(1-(3-((S)-1-(3-(3-Chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl-ca-
rbamoyl)-1H-pyrazol-5-yl)ethoxy)-4-oxobutanoic acid;
(S)-5-Chloro-N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)-propan-2-y-
l)pyrazine-2-carboxamide;
N--((S)-1-(3-(3-Chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-1-((S)-
-2-hydroxypropyl)-2-methyl-1H-imidazole-4-carboxamide;
(S)-1-Butyl-N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-
-2-methyl-1H-imidazole-4-carboxamide;
(S)--N-(1-(3-(3-Chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-5-(2-h-
ydroxypropan-2-yl)-1H-pyrazole-3-carboxamide;
(S)--N-(1-(3-(3-Chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-1'-met-
hyl-1'H-1,4'-bipyrazole-3-carboxamide;
N--((S)-1-(3-(3-Chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-1-((R)-
-2-hydroxypropyl)-2-methyl-1H-imidazole-4-carboxamide;
(S)-2-Bromo-N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)-propan-2-yl-
)-1H-imidazole-4-carboxamide;
N--((S)-1-(3-(3-Chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-5-(1-h-
ydroxy-2-methylpropyl)isoxazole-3-carboxamide;
(S)--N-(1-(3-(3-Chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-1-(2-c-
yanoethyl)-2-methyl-1H-imidazole-4-carboxamide;
N--((S)-1-(3-(3-Chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-1-(1-c-
yanoethyl)-2-methyl-1H-imidazole-4-carboxamide;
(S)--N-(1-(3-(3-Chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-1-(2-m-
ethylprop-1-enyl)-1H-pyrazole-3-carboxamide;
(S)--N-(1-(3-(3-Chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-3-(1H--
imidazol-4-yl)-1H-pyrazole-5-carboxamide;
(S)--N-(1-(3-(3-Chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-1-cycl-
opropyl-1H-pyrazole-3-carboxamide;
(S)--N-(1-(3-(3-Chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-1-(6-(-
dimethylamino)pyridin-3-yl)-1H-pyrazole-3-carboxamide;
(S)--N-(1-(3-(3-Chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-4,5,6,-
7-tetrahydropyrazolo[1,5-a]pyridine-2-carboxamide);
N--((S)-1-(3-(3-Chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-2-(1-h-
ydroxyethyl)-1H-imidazole-4-carboxamide;
(S)--N-(1-(3-(3-Chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-2-isop-
ropyl-1H-imidazole-4-carboxamide;
(S)-2-Butyl-N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-
-1-methyl-1H-imidazole-4-carboxamide;
(S)--N-(1-(3-(3-Chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-2-(2-h-
ydroxypropan-2-yl)-1-methyl-1H-imidazole-4-carboxamide;
(S)--N-(1-(3-(3-Chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-1-meth-
yl-2-(1-methyl-1H-pyrazol-4-yl)-1H-imidazole-4-carboxamide;
(S)--N-(1-(3-(3-Chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-2-cycl-
opropyl-1-methyl-1H-imidazole-4-carboxamide;
(S)--N.sup.4-(1-(3-(3-Chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)--
1H-imidazole-2,4-dicarboxamide;
(S)--N-(1-(3-(4-Cyano-3-(trifluoromethyl)phenyl)-1H-pyrazol-1-yl)propan-2-
-yl)-2-(2-hydroxypropan-2-yl)oxazole-4-carboxamide
and pharmaceutically acceptable salts thereof.
Further examples of preferred compounds of formula (I) or (II)
include
(S)--N-(2-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propyl)-2--
(2-hydroxypropan-2-yl)oxazole-4-carboxamide;
(R)--N-(2-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propyl)-2--
(2-hydroxypropan-2-yl)oxazole-4-carboxamide;
(R)--N-(2-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propyl)-2--
(2-hydroxypropan-2-yl)-1H-imidazole-4-carboxamide;
(S)--N-(1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-y-
l)-2-(2,2,2-trifluoroethyl)-1H-imidazole-4-carboxamide;
(S)--N-(1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-y-
l)-2-(trifluoromethyl)-1H-imidazole-4-carboxamide;
N--((S)-1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-y-
l)-3-((S)-1-hydroxyethyl)-1,2,4-oxadiazole-5-carboxamide;
N--((S)-1-(3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-y-
l)-3-((R)-1-hydroxyethyl)-1,2,4-oxadiazole-5-carboxamide;
(S)--N-(2-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propyl)-3--
(2-hydroxypropan-2-yl)-1,2,4-oxadiazole-5-carboxamide;
(S)--N-(1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-y-
l)-3-(2-hydroxypropan-2-yl)-1,2,4-oxadiazole-5-carboxamide;
(S)--N-(1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-y-
l)-2-cyclopropyl-1H-imidazole-4-carboxamide;
(S)--N.sup.4-(1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)prop-
an-2-yl)-N.sup.2,N.sup.2-dimethyl-1H-imidazole-2,4-dicarboxamide;
(S)--N-(1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-y-
l)-2-(2-ethoxypropan-2-yl)-1H-imidazole-4-carboxamide;
N--((S)-1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-y-
l)-2-(1-ethoxyethyl)-1H-imidazole-4-carboxamide;
(S)--N-(1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-y-
l)-2-(2-ethoxypropan-2-yl)oxazole-4-carboxamide;
(S)--N-(1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-y-
l)-5-(2-hydroxy-2-methylpropyl)-1H-pyrazole-3-carboxamide
and pharmaceutically acceptable salts thereof.
Compounds of the invention may be administered to a patient in
therapeutically effective amounts which range usually from about
0.1 to about 5000 mg, preferably from about 1 to about 2000 mg, per
day depending on the age, weight, ethnic group, condition of the
patient, condition to be treated, administration route and the
androgen (AR) modulator used. The compounds of the invention can be
formulated into dosage forms using the principles known in the art.
It can be given to a patient as such or in combination with
suitable pharmaceutical excipients in the form of tablets,
granules, capsules, suppositories, emulsions, suspensions or
solutions. Choosing suitable ingredients for the composition is a
routine for those of ordinary skill in the art. It is evident that
suitable carriers, solvents, gel forming ingredients, dispersion
forming ingredients, antioxidants, colours, sweeteners, wetting
compounds and other ingredients normally used in this field of
technology may be also used. The compositions containing the active
compound can be given enterally or parenterally, the oral route
being the preferred way. The contents of the active compound in the
composition is from about 0.5 to 100%, preferably from about 1 to
about 85%, per weight of the total composition.
The compounds of the invention can be given to the subject as the
sole active ingredient or in combination with one of more other
active ingredients suitable for the treatment or prevention of an
AR dependent condition, e.g. AR dependent cancer such as prostate
cancer, and other diseases where AR antagonism is desired.
The present invention will be explained in more detail by the
following examples. The examples are meant only for illustrating
purposes and do not limit the scope of the invention defined in
claims.
EXAMPLES
The end products of the following Examples were prepared as a
mixture of diastereomers unless otherwise indicated.
Example 1
(S)--N-(1-(3-(3-Chloro-4-cyano-2,5-difluorophenyl)-1H-pyrazol-1-yl)propan--
2-yl)-2-methyl-1H-imidazole-5-carboxamide
a) 4-Bromo-2-chloro-3,6-difluoroaniline
2-Chloro-3,6-difluoroaniline (18.34 mmol, 3 g) was dissolved in ACN
and cooled to 0.degree. C. with an ice bath. A solution of
N-bromosuccinimide (18.34 mmol, 3.26 g) dissolved in ACN was added
using a dropping funnel maintaining the internal temperature of the
reaction mixture below 5.degree. C. After addition the mixture was
stirred for 15 min letting the temperature slowly rise to ambient
temperature. The reaction mixture was diluted with 10% aq.
NaHSO.sub.3, stirred for 10 min and evaporated to 1/3 of the
original volume. The residue was diluted with water and extracted
twice with excess of ethyl acetate. The organics were dried,
filtered and evaporated. The product was purified with flash
chromatography. 4.087 g of the title compound was obtained.
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. 5.97 (s, 2H),
7.42-7.52 (m, 1H).
b)
2-Chloro-3,6-difluoro-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)--
aniline
4-Bromo-2-chloro-3,6-difluoroaniline (12.37 mmol, 3 g) and
1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-5-boronic acid pinacol
ester (12.37 mmol, 3.44 g) were dissolved in DME.
Bis(triphenylphosphine)palladium(II) chloride (0.619 mmol, 0.434 g)
and sodium carbonate, 2 M solution (12.37 mmol, 1.311 g) were
added. The reaction mixture was refluxed at 80.degree. C. for 4 h
and the stirring was continued at 50.degree. C. overnight. The
solvent was evaporated and the residue was extracted three times
with EtOAc. The combined organics were washed with water and brine.
The organics were dried, filtered and evaporated. The crude product
was purified by flash chromatography. 1.935 g of the title compound
was obtained. .sup.1H-NMR (400 MHz, MeOH-d.sub.4): .delta.
1.49-1.79 (m, 2H), 1.80-1.88 (m, 1H), 1.93-2.19 (m, 2H), 2.33-2.47
(m, 1H), 3.47-3.77 (m, 1H), 3.96-4.07 (m, 1H), 5.09-5.43 (m, 1H),
6.30-6.39 (m, 1H), 7.04-7.13 (m, 1H), 7.50-7.63 (m, 1H).
c)
5-(3-Chloro-2,5-difluoro-4-iodophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H--
pyrazole
Copper(I) iodide (7.43 mmol, 1.415 g) and tert-butyl nitrite (10.40
mmol, 1.073 g) were stirred in ACN. The mixture was warmed to
75.degree. C.
2-Chloro-3,6-difluoro-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)ani-
line (6.17 mmol, 1.935 g) dissolved in ACN was added dropwise
during 20 min. The resulting mixture was stirred for 6 h at
75.degree. C. The mixture was cooled to RT and a solution of
aqueous sodium thiosulfate was added. The mixture was extracted
three times with ethyl acetate. The combined organics were washed
with brine, dried, filtered and evaporated. The crude product was
purified by flash chromatography. 0.716 g of the title compound was
obtained. .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. 1.48-1.74
(m, 3H), 1.81-2.02 (m, 2H), 2.30-2.44 (m, 1H), 3.47-3.58 (m, 1H),
3.86-3.96 (m, 1H), 5.28 (dd, 1H), 6.60-6.65 (m, 1H), 7.46-7.52 (m,
1H), 7.69-7.72 (m, 1H).
d)
2-Chloro-3,6-difluoro-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)--
benzonitrile
5-(3-Chloro-2,5-difluoro-4-iodophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-py-
razole (1.686 mmol, 0.716 g) and copper(I) cyanide (1.686 mmol,
0.151 g) were suspended in NMP. The resulting mixture was stirred
at 170.degree. C. for 7 h. The reaction was quenched by, pouring
the mixture onto 12% ammonia solution and stirred for 20 min. The
formed precipitate was filtered and washed with water. 0.276 g of
the title product was obtained. Identification after the next step
due to low solubility of the product.
e) 2-Chloro-3,6-difluoro-4-(1H-pyrazol-5-yl)benzonitrile
2-Chloro-3,6-difluoro-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)-be-
nzonitrile (0.853 mmol, 0.276 g) was stirred in ethanol. 10%
HCl/EtOH solution (5 ml) was slowly added. The resulting mixture
was stirred at RT overnight. The reaction mixture was neutralized
with NaHCO.sub.3 and extracted twice with EtOAc. The combined
organics were washed with water, dried, filtered and evaporated.
0.219 g of the title compound was obtained. .sup.1H-NMR (400 MHz,
DMSO-d.sub.6): .delta. 6.86 (bs, 1H), 7.88-8.10 (m, 2H), 13.57 (bs,
1H).
f)
(S)-4-(1-(2-Aminopropyl)-1H-pyrazol-3-yl)-2-chloro-3,6-difluorobenzonit-
rile
2-Chloro-3,6-difluoro-4-(1H-pyrazol-5-yl)benzonitrile (0.835 mmol,
0.2 g) was dissolved in THF under nitrogen atmosphere.
(S)-tert-butyl (1-hydroxypropan-2-yl)carbamate (0.835 mmol, 0.146
g) and triphenylphosphine (1.252 mmol, 0.328 g) were dissolved in
THF and added to the previous mixture. The resulting mixture was
cooled to 0.degree. C. Di-tert-butyl azodicarboxylate (1.252 mmol,
0.288 g) was added in small portions and stirred under cold
conditions for 10 min. The flask was warmed to RT and stirred
overnight. The solvent was evaporated. The residue was dissolved in
ethanol and 10% HCl(g)/EtOH solution (15 ml) was slowly added. The
resulting mixture was stirred overnight. The mixture was diluted
with water and extracted twice with DCM. The combined organics were
washed with water. The aqueous phases were combined and the pH was
adjusted to 12 with 2 M NaOH. The aqueous phase was extracted three
times with DCM. The combined organics were dried, filtered and
evaporated. 0.167 g of the title compound was obtained. .sup.1H-NMR
(400 MHz, CDCl.sub.3): .delta. 1.17 (d, 3H), 1.31 (bs, 2H), 3.53
(bs, 1H), 3.88-4.04 (m, 1H), 4.09-4.26 (m, 1H), 6.82 (dd, 1H), 7.55
(d, 1H), 7.88 (dd, 1H).
g)
(S)--N-(1-(3-(3-Chloro-4-cyano-2,5-difluorophenyl)-1H-pyrazol-1-yl)-pro-
pan-2-yl)-2-methyl-1H-imidazole-5-carboxamide
2-Methyl-1H-imidazole-4-carboxylic acid (0.202 mmol, 0.026 g) was
dissolved in DMF (5 ml) under nitrogen atmosphere. EDCI (0.202
mmol, 0.039 g), DIPEA (0.270 mmol, 0.035 g) and HBTU (0.034 mmol,
0.013 g) were added and the resulting mixture was stirred for 20
min at RT.
(S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-3,6-difluorobenzonitri-
le (0.135 mmol, 0.04 g) dissolved in DMF (2 ml) was added and the
resulting mixture was stirred at RT for 3 days. The mixture was
diluted with water and EtOAc, washed with 2M Na.sub.2CO.sub.3,
water and brine. The combined organics were dried, filtered and
evaporated. The crude product was purified by flash chromatography.
0.0324 g of the title compound was obtained. .sup.1H-NMR (400 MHz,
MeOH-d.sub.4) .delta. ppm 1.23 (d, 3H), 2.38 (s, 3H), 4.28-4.47 (m,
2H), 4.48-4.58 (m, 1H), 6.77-6.82 (m, 1H), 7.46 (s, 1H), 7.77 (d,
1H), 7.83-7.96 (m, 1H).
Example 2
(S)--N-(1-(3-(3-Chloro-4-cyano-2,5-difluorophenyl)-1H-pyrazol-1-yl)-propan-
-2-yl)-2-(2-hydroxypropan-2-yl)oxazole-5-carboxamide
a) Ethyl 2-chlorooxazole-4-carboxylate
Ethyl 2-aminooxazole-4-carboxylate (20 g, 128 mmol) was added to a
solution of cupric chloride (32.8 g, 192 mmol) and t-butylnitrite
(23 ml, 192 mmol) in ACN (500 ml) at 80.degree. C. and the
resulting mixture was refluxed for 4 h. The reaction mixture was
concentrated and treated with concentrated HCl and extracted with
EtOAc. The product was purified with flash chromatography. Yield
10.5 g. .sup.1H-NMR (400 MHz; CDCl.sub.3): .delta. 1.36 (t, 3H),
4.39 (q, 2H), 8.47 (s, 1H).
b) Ethyl 2-(1-ethoxyvinyl)oxazole-4-carboxylate
Ethyl 2-(1-ethoxyvinyl)oxazole-4-carboxylate was prepared using the
procedure described in Example 33(a), starting from ethyl
2-chlorooxazole-4-carboxylate (10.5 g, 59.8 mmol) and
tributyl(1-ethoxyvinyl)stannane (24 ml, 65.8 mmol), The product was
purified with flash-chromatography. Yield 10.3 g. .sup.1H-NMR (400
MHz; CDCl.sub.3): .delta. ppm 1.23-1.46 (m, 6H), 3.94-3.99 (m, 2H),
4.36-4.42 (m, 2H), 4.8 (d, 1H), 5.33 (s, 1H), 8.19 (s, 1H).
c) Ethyl 2-acetyloxazole-4-carboxylate
Ethyl 2-acetyloxazole-4-carboxylate was prepared using the
procedure described in Example 33(b), starting from ethyl
2-(1-ethoxyvinyl)oxazole-4-carboxylate (10.3 g, 48.8 mmol). Yield
7.0 g. .sup.1H-NMR (400 MHz; CDCl.sub.3): .delta. 1.46 (t, 3H),
2.73 (s, 3H), 4.41 (q, 2H), 8.34 (s, 1H).
d) Ethyl 2-(2-hydroxypropan-2-yl)oxazole-4-carboxylate
Into a flask containing a solution of ethyl
2-acetyloxazole-4-carboxylate (2.0 g, 10.9 mmol) in THF (50 ml), 3M
solution of MeMgI in ether (5.0 ml, 13.11 mmol) was added at
0.degree. C. The resulting mixture was stirred at RT for 5 h. The
mixture was quenched with aqueous NH.sub.4Cl solution and extracted
with EtOAc. The organic layer was concentrated and purified with
flash chromatography. Yield 1.0 g. .sup.1H-NMR (400 MHz;
CDCl.sub.3): .delta. 1.59 (s, 3H), 1.66 (s, 6H), 2.70 (s, 1H), 4.39
(q, 2H), 8.17 (s, 1H).
e) 2-(2-Hydroxypropan-2-yl)oxazole-4-carboxylic acid
2-(2-Hydroxypropan-2-yl)oxazole-4-carboxylic acid was prepared
using the procedure described in Example 32(d) starting from ethyl
2-(2-hydroxypropan-2-yl)oxazole-4-carboxylate (1.0 g, 5.02 mmol).
Yield 500 mg. .sup.1H-NMR (400 MHz; DMSO-d.sub.6): .delta. 1.50 (s,
6H), 5.67 (s, 1H), 8.67 (s, 1H), 12.98 (s, 1H).
f)
(S)--N-(1-(3-(3-Chloro-4-cyano-2,5-difluorophenyl)-1H-pyrazol-1-yl)-pro-
pan-2-yl)-2-(2-hydroxypropan-2-yl)oxazole-5-carboxamide
2-(2-Hydroxypropan-2-yl)oxazole-4-carboxylic acid (0.514 mmol,
0.088 g) was dissolved in DMF (10 ml) under nitrogen atmosphere.
EDCI (0.514 mmol, 0.098 g), DIPEA (0.856 mmol, 0.111 g) and HOBt
(0.214 mmol, 0.029 g) were added and the resulting mixture was
stirred for 20 min at RT.
(S)-4-(1-(2-amino-propyl)-1H-pyrazol-3-yl)-2-chloro-3,6-difluorobenzonitr-
ile (0.428 mmol, 0.127 g) dissolved in DMF (5 ml) was added and the
resulting mixture was stirred at RT for 3 days. The mixture was
diluted with water and EtOAc, washed with 2 M Na.sub.2CO.sub.3,
water and brine. The combined organics were dried, filtered and
evaporated. The crude product was purified by flash chromatography.
0.059 g of the title compound was obtained. .sup.1H-NMR (400 MHz,
MeOH-d.sub.4): .delta. 1.26 (d, 3H), 1.61 (s, 6H), 4.34-4.46 (m,
2H), 4.54-4.63 (m, 1H), 6.78-6.82 (m, 1H), 7.76 (d, 1H), 7.87-7.93
(m, 1H), 8.24 (s, 1H).
Example 3
(S)--N-(1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-yl-
)-6-cyanoimidazo[1,2-a]pyridine-2-carboxamide
a) 4-Bromo-3-chloro-5-fluoroaniline
3-Chloro-5-fluoroaniline (2061 mmol, 300 g) was dissolved in ACN
(3000 ml) and the solution cooled to 0.degree. C. NBS (2061 mmol,
367 g) was added to the reaction mixture in small portions keeping
the temperature below 10.degree. C. Reaction mixture was stirred at
10.+-.5.degree. C. for 3.5 h. 10% Aqueous NaHSO.sub.3 was added and
the reaction mixture was concentrated under vacuum to remove
organic solvents. Water and DCM was added, stirred for 15 min and
the phases were separated. The water phase was extracted with DCM.
The combined organics were washed with water. The organic phase was
evaporated. 2-Propanol was added to the residue and distilled until
the steam temperature was 80.degree. C. Water was added and the
temperature was kept at 40.+-.10.degree. C. The mixture was cooled
to 5.degree. C. and stirred for 4 h. The precipitate was removed by
filtration, washed with water and dried under vacuum. 440.7 g of
the title compound was obtained. .sup.1H-NMR (400 MHz,
DMSO-d.sub.6): .delta. 5.87 (s, 2H), 6.42-6.49 (m, 1H), 6.62-6.66
(m, 1H).
b) 4-Amino-2-chloro-6-fluorobenzonitrile
4-Bromo-3-Chloro-5-fluoroaniline (980 mmol, 220 g),
copper(I)cyanide (980 mmol, 88 g) and NMP (1000 ml) were added into
the reaction flask, heated up to 160.degree. C. and stirred for 3 h
to complete the reaction. The reaction mixture was cooled to RT.
Water and 25% ammonia solution was added keeping the mixture at RT.
The mixture was stirred overnight and the formed precipitate was
separated by filtration and flushed with water. The filtered
precipitate was dried under vacuum to give 117.7 g of the title
compound. .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. 6.41-6.47
(m, 1H), 6.58-6.62 (m, 1H), 6.86 (bs, 2H).
c) 2-Chloro-6-fluoro-4-iodobenzonitrile
4-Amino-2-chloro-6-fluorobenzonitrile (293 mmol, 50 g) was
dissolved in ACN (1550 ml) and water (460 ml). Sulphuric acid (879
mmol, 46.9 ml) was added carefully. The reaction mixture was cooled
to 0.degree. C. Sodium nitrite (322 mmol, 22.25 g) dissolved in
water (150 ml) was slowly added keeping the reaction temperature
below 10.degree. C. Thereafter potassium iodide (586 mmol, 97 g)
dissolved in 150 ml of water was added slowly while keeping the
reaction temperature below 10.degree. C. The reaction mixture was
allowed to warm up to RT and stirred overnight at RT. The phases
were separated and the organic phase was evaporated. Ethyl acetate
was added into the evaporation residue and washed three times with
10% aqueous NaHSO.sub.3. The organic phase was evaporated and the
residue was dissolved in DCM. 5 g of active carbon was added and
stirred for 2 h. The mixture was filtered through a layer of Celite
and washed with DCM. The DCM-phase was evaporated and heptanes were
added into the residue. The mixture was heated to 60.degree. C. and
stirred for 2 h. The oil and heptanes layers were separated by
decantation. The heptanes phase was evaporated and 39.6 g of the
title compound was obtained. .sup.1H-NMR (400 MHz, DMSO-d.sub.6):
.delta. 8.06-8.10 (m, 1H), 8.10-8.11 (m, 1H).
d)
2-Chloro-6-fluoro-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)benzo-
nitrile
2-Chloro-6-fluoro-4-iodobenzonitrile (291 mmol, 82 g), THF (800 ml)
and 1-(tetra-hydro-2H-pyran-2-yl)-1H-pyrazole-5-boronic acid
pinacol ester (350 mmol, 97 g) were added into a flask and stirred.
Bis(triphenylphosphine)palladium(II) chloride (14.57 mmol, 10.22
g), sodium carbonate (699 mmol, 74.1 g) and water (350 ml) were
added. The resulting mixture was heated to 60.degree. C. and
stirred for 2 h. The solvents were evaporated. Water was added and
the mixture was left to stir overnight. EtOAc and water were added
and the insoluble precipitates were removed by filtration. The
organic phase was separated from the filtrate and the water phase
was extracted with more EtOAc. The combined organics were
evaporated and the residue was combined with previously filtrated
solid. The collected solids were suspended in EtOH and water. The
mixture was heated to boiling point, allowed to cool to RT and
stirred for an hour at ambient temperature. The mixture was cooled
to 0.degree. C. and stirred for another hour. The precipitate was
washed with a small amount of cold 1:1 water/EtOH. The filtered
solids were dried under vacuum. 91.2 g of the title compound was
obtained. .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. 1.50-1.70
(m, 3H), 1.79-1.89 (m, 1H), 1.92-2.03 (m, 1H), 2.30-2.44 (m, 1H),
3.56-3.67 (m, 1H), 3.93-4.02 (m, 1H), 5.36 (dd, 1H), 6.78 (d, 1H),
7.66 (d, 1H), 7.73 (dd, 1H), 7.80-7.83 (m, 1H).
e) 2-Chloro-6-fluoro-4-(1H-pyrazol-5-yl)benzonitrile
hydrochloride
2-Chloro-6-fluoro-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)benzo-n-
itrite (298 mmol, 91 g) and 10% HCl/EtOH (339 ml) were mixed in a
flask under nitrogen atmosphere. The resulting mixture was refluxed
for 5 h during which 113 ml of 10% HCl/EtOH was added. The mixture
was cooled to RT and stirred overnight. Next morning 40 ml of 10%
HCl/EtOH was added and the mixture was refluxed for 3.5 h, cooled
to 0.degree. C. and stirred for an hour. The precipitate was
removed by filtration and dried under vacuum. Half of the solvents
in filtrate were evaporated and the remaining mixture was stirred
at 0.degree. C. for 3 h. The precipitates were again removed by
filtration and dried under vacuum. The collected solids were
combined to afford 51.8 g of the title compound. .sup.1H-NMR (400
MHz, DMSO-d.sub.6): .delta. 7.06 (d, 1H), 7.88 (d, 1H), 7.95 (dd,
1H), 8.03-8.07 (m, 1H).
f) 2-Chloro-6-fluoro-4-(1H-pyrazol-5-yl)benzonitrile
2-Chloro-6-fluoro-4-(1H-pyrazol-5-yl)benzonitrile hydrochloride
(201 mmol, 51.8 g) was dissolved in THF (510 ml). Sodium hydroxide
50% (401 mmol, 32.1 g) was added and the resulting mixture was
stirred at RT for 3 h. Almost all the solvents were evaporated and
water was added to the residue. The mixture was stirred overnight
at RT. The precipitate was removed by filtration the solid was
flushed twice with water. The solid was dried under vacuum. 35.8 g
of the title compound was obtained. .sup.1H-NMR (400 MHz,
DMSO-d.sub.6): .delta. 7.05 (d, 1H), 7.88-7.97 (m, 2H), 8.02-8.07
(m, 1H), 13.37 (bs, 1H).
g)
(S)-4-(1-(2-Aminopropyl)-1H-pyrazol-3-yl)-2-chloro-6-fluorobenzonitrile
(S)-tert-Butyl (1-hydroxypropan-2-yl)carbamate (259 mmol, 45.4 g)
and triphenylphosphine (259 mmol, 68.0 g) were mixed in dry EtOAc
(380 ml) under nitrogen atmosphere.
2-Chloro-6-fluoro-4-(1H-pyrazol-3-yl)benzonitrile (130 mmol, 35.9
g) was added and the resulting mixture was stirred for 10 min. DIAD
(259 mmol, 52.4 g) was added slowly while keeping the temperature
between 15-25.degree. C. with an ice bath. After the addition the
mixture was allowed to warm to RT and stirred for 4 h. Water and
concentrated HCl (1296 mmol, 106 ml) was added to the mixture and
stirred for 6 days during which more HCl (107 ml in total) was
added. Water and DCM was added and the mixture was stirred for a
while before separating the phases. The organic phase was extracted
twice with water. The water phases were combined and washed twice
with DCM. DCM was added to the water phase and the pH of the water
phase was adjusted to 12.5 with 50% NaOH. The phases were separated
and the water phase was extracted once more with DCM. The DCM
phases were combined and washed once with water. The separated DCM
phase was evaporated and dried under vacuum. 24.0 g of the title
compound was obtained. .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta.
0.96 (d, 3H), 1.18 (bs, 2H), 3.19-3.29 (m, 1H), 3.97-4.08 (m, 2H),
7.03 (d, 1H), 7.85-7.92 (m, 2H), 7.98-8.02 (m, 1H).
h)
(S)--N-(1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-
-yl)-6-cyanoimidazo[1,2-a]pyridine-2-carboxamide ORM-19702
6-Cyanoimidazo[1,2-a]pyridine-2-carboxylic acid (0.770 mmol, 0.144
g), HOBt (0.770 mmol, 0.104 g) and DIPEA (1.539 mmol, 0.199 g) were
dissolved in DCM (5 ml) and DMF (1 ml). EDCI (0.770 mmol, 0.148 g)
was added and the resulting mixture was stirred for 10 min at RT.
(S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-6-fluorobenzonitrile
(0.592 mmol, 0.22 g) dissolved in small amount of DCM was added and
the reaction mixture was stirred overnight at RT. The mixture was
diluted with DCM, washed with 1M Na.sub.2CO.sub.3 and water. The
organic phase was dried, filtered and evaporated. The crude product
was purified by trituration from ACN. 0.054 g of the title compound
was obtained. .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. 1.15 (d,
3H), 4.31-4.45 (m, 2H), 4.46-4.57 (m, 1H), 7.00 (d, 1H), 7.61-7.66
(m, 1H), 7.72-7.77 (m, 1H), 7.86-7.92 (m, 2H), 7.93-7.96 (m, 1H),
8.35-8.37 (m, 1H), 8.69 (d, 1H), 9.34-9.37 (m, 1H).
Example 4
(S)--N-(1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-yl-
)-7-oxo-5,6,7,8-tetrahydroimidazo[1,2-a]pyrimidine-2-carboxamide
a) Ethyl
7-oxo-5,6,7,8-tetrahydroimidazo[1,2-a]pyrimidine-2-carboxylate
Ethyl 2-amino-1H-imidazole-4-carboxylate (6.45 mmol, 1 g) and
triethylamine (10.04 mmol, 1.016 g) were suspended in dry ACN (30
ml) and cooled to 0.degree. C. Acryloyl chloride (9.67 mmol, 0.875
g) dissolved in dry ACN (4 ml) was added dropwise. The resulting
mixture was slowly warmed to RT and subsequently heated to
50.degree. C. for 16 h. The solvent was evaporated and the residue
purified by flash chromatography. 0.358 g of the title compound was
obtained. .sup.1H-NMR (400 MHz, CDCl.sub.3): .delta. 1.37 (t, 3H),
2.92 (t, 2H), 4.18 (t, 2H), 4.37 (q, 2H), 7.40 (s, 1H), 8.78 (bs,
1H).
b) 7-Oxo-5,6,7,8-tetrahydroimidazo[1,2-a]pyrimidine-2-carboxylic
acid
Ethyl
7-oxo-5,6,7,8-tetrahydroimidazo[1,2-a]pyrimidine-2-carboxylate
(1.711 mmol, 0.358 g) was dissolved in ethanol (5 ml) and cooled to
0.degree. C. 1N solution of NaOH (5 ml) was slowly added. The
resulting mixture was heated to 60.degree. C. for 1.5 h. Ethanol
was evaporated, the residue diluted with tert-butyl methyl ether
and acidified with 2 N HCl solution under cold conditions. The
mixture was stirred for overnight. DCM and water was added and the
precipitate was filtered. Phases in the filtrate were separated and
the water phase was evaporated. The residue from water and
precipitate were combined. 0.592 g of the title compound was
obtained. .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. 2.73 (t,
2H), 4.12 (t, 2H), 7.58 (s, 1H), 11.09 (bs, 1H).
c)
(S)--N-(1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-
-yl)-7-oxo-5,6,7,8-tetrahydroimidazo[1,2-a]pyrimidine-2-carboxamide
7-Oxo-5,6,7,8-tetrahydroimidazo[1,2-a]pyrimidine-2-carboxylic acid
(1.513 mmol, 0.274 g) was dissolved in DMF (5 ml) under nitrogen
atmosphere. EDCI (1.891 mmol, 0.362 g), DIPEA (3.78 mmol, 0.489 g)
and HOBt (1.891 mmol, 0.255 g) were added and the resulting mixture
was stirred for 20 min at RT.
(S)-4-(1-(2-Aminopropyl)-1H-pyrazol-3-yl)-2-chloro-6-fluorobenzonitrile
(1.260 mmol, 0.351 g) dissolved in DMF (5 ml) was added and the
resulting mixture was stirred at RT for 2 days. The mixture was
diluted with water and EtOAc, washed with 2M Na.sub.2CO.sub.3,
water and brine. The combined organics were dried, filtered and
evaporated. The crude product was purified by preparative HPLC.
0.0089 g of the title compound was obtained. .sup.1H-NMR (400 MHz,
CDCl.sub.3): .delta. 1.28 (d, 3H), 2.89 (t, 2H), 4.16 (t, 2H),
4.33-4.39 (m, 2H), 4.54-4.65 (m, 1H), 6.59 (d, 1H), 7.36 (s, 1H),
7.53 (d, 1H), 7.57 (dd, 1H), 7.72-7.75 (m, 1H), 7.83 (d, 1H).
Example 5
(S)--N-(1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-yl-
)-3-isopropyl-1,2,4-oxadiazole-5-carboxamide
a) Ethyl 3-isopropyl-1,2,4-oxadiazole-5-carboxylate
(E)-N'-hydroxyisobutyrimidamide (27.6 mmol, 2.82 g) was dissolved
in pyridine (10 ml) and cooled to 0.degree. C. Ethyl oxalyl
chloride (35.9 mmol, 4.90 g) was added dropwise to the previous
mixture and stirred for 10 min at 0.degree. C., warmed to RT and
later heated to 70.degree. C. for 1.5 h. The mixture was poured to
ice-cold water. The residue was extracted twice with t-butyl methyl
ether and water. The organic phase was dried, filtered and
evaporated. The crude product was purified by flash chromatography.
1.919 g of the title compound was obtained. .sup.1H-NMR (400 MHz,
CDCl.sub.3): .delta. 1.39 (d, 6H), 1.47 (t, 3H), 3.14-3.28 (m, 1H),
4.54 (q, 2H).
b) 3-Isopropyl-1,2,4-oxadiazole-5-carboxylic acid
Ethyl 3-isopropyl-1,2,4-oxadiazole-5-carboxylate (10.42 mmol, 1.919
g) was dissolved in EtOH (20 ml). Sodium hydroxide pellets (12.50
mmol, 0.500 g) were dissolved in cold water (10 ml) and solution
slowly added. The resulting solution was heated at 60.degree. C.
for 1.5 h. EtOH was removed under vacuum. The residue was diluted
with tert-butyl methyl ether. The mixture was acidified under cold
conditions by adding 2 N HCl solution. The mixture was stirred
overnight and washed with DCM. Water phase was evaporated
precipitating the product. 1.673 g of the title compound was
obtained. .sup.1H-NMR (400 MHz, D.sub.2O): .delta. 1.33 (d, 6H),
3.10-3.25 (m, 1H).
c)
(S)--N-(1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-
-yl)-3-isopropyl-1,2,4-oxadiazole-5-carboxamide
3-Isopropyl-1,2,4-oxadiazole-5-carboxylic acid (1.281 mmol, 0.2 g)
was dissolved in DMF (5 ml) under nitrogen atmosphere. EDCI (1.601
mmol, 0.307 g), DIPEA (3.20 mmol, 0.414 g) and HOBt (1.601 mmol,
0.216 g) were added and the resulting mixture was stirred for 20
min at RT.
(S)-4-(1-(2-Aminopropyl)-1H-pyrazol-3-yl)-2-chloro-6-fluorobenzonitrile
(1.067 mmol, 0.298 g) dissolved in DMF (5 ml) was added and the
resulting mixture was stirred at RT for 2 days. The mixture was
diluted with water and EtOAc, washed with 2 M Na.sub.2CO.sub.3,
water and brine. The combined organics were dried, filtered and
evaporated. The crude product was purified by preparative HPLC.
0.0056 g of the title compound was obtained. .sup.1H-NMR (400 MHz,
CDCl.sub.3): .delta. 1.25 (d, 3H), 1.38 (d, 6H), 3.11-3.26 (m, 1H),
4.26-4.35 (m, 1H), 4.41-4.50 (m, 1H), 4.55-4.67 (m, 1H), 6.65-6.69
(m, 1H), 7.54-7.57 (m, 1H), 7.64-7.69 (m, 1H), 7.74-7.77 (m, 1H),
8.39 (d, 1H).
Example 6
(S)--N-(1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-yl-
)-5,7-dimethylimidazo[1,2-c]pyrimidine-2-carboxamide
a) Ethyl 5,7-dimethylimidazo[1,2-c]pyrimidine-2-carboxylate
4-Amino-2,6-dimethylpyrimidine (16.24 mmol, 2 g) was mixed with
ethanol (30 ml) and stirred well. Ethyl bromopyruvate (20.30 mmol,
3.96 g) was added in small portions. The resulting mixture was
refluxed for 5.5 h and stirred at RT overnight. The solvent was
evaporated, DCM was added and washed with Na.sub.2HCO.sub.3. The
organic phase was dried, filtered and evaporated. The crude product
was purified by flash chromatography and trituration from
EtOAc/heptane, respectively. 0.287 g of the title product was
obtained. .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. 1.33 (t,
3H), 2.42 (d, 3H), 2.80 (s, 3H), 4.33 (q, 2H), 7.32 (s, 1H), 8.50
(d, 1H).
b) 5,7-Dimethylimidazo[1,2-c]pyrimidine-2-carboxylic acid
Ethyl 5,7-dimethylimidazo[1,2-c]pyrimidine-2-carboxylate (1.268
mmol, 0.278 g) was dissolved in ethanol (10 ml) and cooled to
0.degree. C. 2 M NaOH solution was added to the reaction mixture.
The resulting mixture was stirred at 0.degree. C. for 30 min and
for an hour at RT. The solvent was evaporated and water added to
the residue. The water phase was made acidic with 1 M HCl and
extracted three times with EtOAc. The combined organics were dried,
filtered and evaporated. 0.292 g of the title compound was
obtained. .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. 2.46 (s,
3H), 2.83 (s, 3H), 7.39 (s, 1H), 8.57 (s, 1H).
c)
(S)--N-(1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-
-yl)-5,7-dimethylimidazo[1,2-c]pyrimidine-2-carboxamide
The title compound was prepared using the procedure described in
Example 3(h) starting from
5,7-dimethyl-imidazo[1,2-c]pyrimidine-2-carboxylic acid (0.753
mmol, 0.144 g) and
(S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-6-fluoro-benzonitrile
(0.538 mmol, 0.2 g). DMF (6 ml) was used as a solvent and HBTU
(0.054 mmol, 0.020 g) was used instead of HOBt. The crude product
was purified by trituration from ACN. 0.045 g of the title compound
was obtained. .sup.1H-NMR (400 MHz, CDCl.sub.3): .delta. 1.26 (d,
3H), 2.53-2.56 (m, 3H), 2.82 (s, 3H), 4.30 (dd, 1H), 4.48 (dd, 1H),
4.60-4.72 (m, 1H), 6.63 (d, 1H), 7.23-7.26 (m, 1H), 7.52 (d, 1H),
7.75-7.83 (m, 2H), 8.00-8.06 (m, 1H), 8.27 (d, 114).
Example 7
(S)-5-((1H-Imidazol-1-yl)methyl)-N-(1-(3-(3-chloro-4-cyano-5-fluorophenyl)-
-1H-pyrazol-1-yl)propan-2-yl)isoxazole-3-carboxamide
a) 5-(Bromomethyl)isoxazole-3-carboxylic acid
Ethyl 5-(bromomethyl)isoxazole-3-carboxylate (4.27 mmol, 1 g) and
lithium hydroxide (10.68 mmol, 0.256 g) were dissolved in THF (6.5
ml) and water (6.5 ml). The resulting mixture was stirred for 30
min at RT. The pH was adjusted to 4 with 1 M HCl and diluted with
water. The mixture was extracted three times with EtOAc. The
combined organics were dried, filtered and evaporated. 0.543 g of
the title compound was obtained. .sup.1H-NMR (400 MHz,
DMSO-d.sub.6): .delta. 4.88 (s, 2H), 6.92 (s, 1H), 14.09 (bs,
1H).
b)
(S)-5-(Bromomethyl)-N-(1-(3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyrazo-
l-1-yl)propan-2-yl)isoxazole-3-carboxamide
5-(Bromomethyl)isoxazole-3-carboxylic acid (0.718 mmol, 0.148 g)
was dissolved in DCM (5 ml) and THF (1 ml).
1,3-Dicyclohexylcarbodiimide (0.718 mmol, 0.148 g) was added and
the resulting mixture was stirred at RT. The precipitate formed was
filtered and
(S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-6-fluorobenzonitrile
(0.359 mmol, 0.1 g), triethylamine (0.359 mmol, 0.036 g) and dry
DCM (5 ml) was added to the filtrate. The filtrate was stirred at
RT under nitrogen atmosphere for two days during which more
1,3-dicyclohexylcarbodiimide (0.148 g), triethylamine (0.050 ml)
and 5-(bromomethyl)isoxazole-3-carboxylic acid (0.1 g) were added.
The reaction mixture was diluted with DCM and washed with
NaHCO.sub.3. The organic phase was dried, filtered and evaporated.
The crude product was purified with flash chromatography. 0.064 g
of the title compound was obtained. .sup.1H-NMR (400 MHz,
CDCl.sub.3): .delta. 1.25 (d, 3H), 4.00-4.09 (m, 2H), 4.23-4.31 (m,
1H), 4.41-4.48 (m, 1H), 4.53-4.63 (m, 1H), 6.60-6.66 (m, 1H),
6.74-6.78 (m, 1H), 7.48-7.53 (m, 1H), 7.64 (d, 1H), 7.79-7.88 (m,
2H).
c)
(S)-5-((1H-Imidazol-1-yl)methyl)-N-(1-(3-(3-chloro-4-cyano-5-fluorophen-
yl)-1H-pyrazol-1-yl)propan-2-yl)isoxazole-3-carboxamide
(S)-5-(Bromomethyl)-N-(1-(3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyrazol--
1-yl)propan-2-yl)isoxazole-3-carboxamide (0.137 mmol, 0.064 g) was
suspended in DMF (5 ml). Imidazole (2.74 mmol, 0.187 g) was added
and the resulting mixture was stirred at RT for 2.5 h. The reaction
mixture was heated to 60.degree. C. for 1.5 h. The mixture was
diluted with EtOAc and washed four times with water. The organic
phase was dried, filtered and evaporated. The crude product was
purified by preparative HPLC. 0.017 g of the title compound was
obtained. .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. 1.15 (d,
3H), 4.31 (d, 2H), 4.37-4.50 (m, 1H), 5.50 (s, 2H), 6.63 (s, 1H),
6.94 (s, 1H), 6.99 (d, 1H), 7.22-7.24 (m, 1H), 7.76 (s, 1H), 7.83
(d, 1H), 7.84-7.88 (m, 1H), 7.96 (s, 1H), 8.81 (d, 1H).
Example 8
(S)--N-(1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-yl-
)-5-oxo-5,6-dihydroimidazo[1,2-c]pyrimidine-2-carboxamide
a) ethyl
5-oxo-5,6-dihydroimidazo[1,2-c]pyrimidine-2-carboxylate
Ethyl bromopyruvate (18.00 mmol, 3.51 g) was dissolved in ethanol
(50 ml). Cytosine (18.00 mmol, 2 g) was added and the resulting
mixture was refluxed for 5.5 h. The mixture was evaporated and DCM
was added. The precipitate was filtered and washed with water. The
filtrate was washed with NaHCO.sub.3, water and evaporated. The
evaporation residue and the previously filtered precipitate were
purified by flash chromatography and trituration from water,
respectively. 0.526 g of the title compound was obtained.
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. 1.31 (t, 3H), 4.29 (q,
2H), 6.60 (d, 1H), 7.30-7.38 (m, 1H), 8.22 (s, 1H), 11.77 (bs,
1H).
b) 5-Oxo-5,6-dihydroimidazo[1,2-c]pyrimidine-2-carboxylic acid
Ethyl 5-oxo-5,6-dihydroimidazo[1,2-c]pyrimidine-2-carboxylate
(2.510 mmol, 0.52 g) was suspended in ethanol (20 ml). Cesium
carbonate (5.02 mmol, 1.635 g) dissolved in water (4 ml) was added
and the resulting mixture was stirred at RT for 3.5 h after which
the mixture was refluxed for 8 h. The ethanol was evaporated, and
the residue was diluted with water. The pH was adjusted to 4 with 1
M HCl and the solvent was evaporated. The residue was purified by
trituration from DMF. 0.137 g of the title compound was obtained.
.sup.1H-NMR (400 MHz, CDCl.sub.3): .delta. 7.17-7.31 (m, 2H),
7.86-7.99 (m, 1H).
c)
(S)--N-(1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-
-yl)-5-oxo-5,6-dihydroimidazo[1,2-c]pyrimidine-2-carboxamide
5-Oxo-5,6-dihydroimidazo[1,2-c]pyrimidine-2-carboxylic acid (0.323
mmol, 0.058 g), HBTU (0.027 mmol, 10.21 mg), DIPEA (0.323 mmol,
0.042 g) and EDCI (0.323 mmol, 0.062 g) were suspended in DMF (2
ml) and the resulting mixture was stirred at RT for 10 min.
(S)-4-(1-(2-Aminopropyl)-1H-pyrazol-3-yl)-2-chloro-6-fluorobenzonitrile
(0.269 mmol, 0.1 g) dissolved in DMF (2 ml) was added and the
resulting mixture was stirred for 17 h at RT. At this point more
starting materials were added so that the amount of every starting
material was raised by half of the original amount. The amount of
(S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-6-fluorobenzonitrile
was not changed. The reaction was continued for another 22 h after
which the temperature was raised to 80.degree. C. for 4.5 h. The
reaction mixture was diluted with EtOAc and washed with 1M
Na.sub.2CO.sub.3, brine and water. The organic phase was dried,
filtered and evaporated. The crude product was purified by
preparative HPLC. 0.006 g of the title compound was obtained.
.sup.1H-NMR (400 MHz, MeOH-d.sub.4): .delta. 1.25 (d, 3H),
4.30-4.37 (m, 1H), 4.42-4.49 (m, 1H), 4.54-4.65 (m, 1H), 6.61 (dd,
1H), 6.70 (d, 1H), 7.18 (d, 1H), 7.63 (d, 1H), 7.75-7.82 (m, 2H),
8.26 (s, 1H).
Example 9
(S)--N-(1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-yl-
)-1,6-dihydropyrrolo[2,3-c]pyrazole-5-carboxamide
a) Ethyl 1,6-dihydropyrrolo[2,3-c]pyrazole-5-carboxylate
3-Aminopyrazole (1.203 mmol, 0.1 g), ethyl bromopyruvate (1.504
mmol, 0.293 g) and methanol were added into a flask and refluxed
for 1.5 h. The solvent was evaporated and the residue was dissolved
in DCM and washed with Na.sub.2HCO.sub.3. The organic phase was
dried, filtered and evaporated. 0.238 g of the title compound was
obtained. .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. 1.30 (t,
3H), 4.26 (q, 2H), 6.76 (d, 1H), 7.68 (s, 1H).
b) 1,6-Dihydropyrrolo[2,3-c]pyrazole-5-carboxylic acid
Ethyl 1,6-dihydropyrrolo[2,3-c]pyrazole-5-carboxylate (1.328 mmol,
0.238 g) was dissolved in ethanol (10 ml). Cesium carbonate (2.66
mmol, 0.866 g) dissolved in water (2 ml) was added and the
resulting mixture was stirred at RT for a day after which more
cesium carbonate (2.66 mmol, 0.866 g) dissolved in water (2 ml) was
added. The temperature was raised to 80.degree. C. for 7 h. Ethanol
was evaporated and the residue was diluted with water. pH was
adjusted to 4 with 2 M HCl and extracted three times with EtOAc and
washed with water. The combined organics were dried, filtered and
evaporated. 0.041 g of the title compound was obtained. LC-MS
[M+1]: 152.
c)
(S)--N-(1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-
-yl)-1,6-dihydropyrrolo[2,3-c]pyrazole-5-carboxamide
The title compound was prepared using the procedure described in
Example 3(h), starting from
1,6-dihydropyrrolo[2,3-c]pyrazole-5-carboxylic acid (0.280 mmol,
0.042 g) and
(S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-6-fluorobenzo-nitrile
(0.215 mmol, 0.080 g). The crude product was purified by
preparative HPLC. 0.0164 g of the title compound was obtained.
.sup.1H-NMR (400 MHz, MeOH-d.sub.4): .delta. 1.29 (d, 3H),
4.27-4.34 (m, 1H), 4.36-4.43 (m, 1H), 4.50-4.60 (m, 1H), 6.75-6.79
(m, 2H), 7.58 (s, 1H), 7.60-7.65 (m, 1H), 7.69 (d, 1H), 7.79-7.82
(m, 1H).
Example 10
(S)--N-(1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-yl-
)imidazo[2,1-b]thiazole-6-carboxamide
The title compound was prepared using the procedure described in
Example 3(h) starting from imidazo[2,1-b]thiazole-6-carboxylic acid
(1.041 mmol, 0.175 g) and
(S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-6-fluorobenzonitrile
(1.041 mmol, 0.290 g). DMF (10 ml) was used as the solvent and the
reaction time was 2 days. The work up was done by diluting the
reaction mixture with water and ethyl acetate and washing it with
2M Na.sub.2CO.sub.3, water and brine. The combined organics were
dried, filtered and eveaporated. The crude product was purified by
flash chromatography. 0.186 g of the title compound was obtained.
.sup.1H-NMR (400 MHz, MeOH-d.sub.4): .delta. 1.24 (d, 3H),
4.32-4.39 (m, 1H), 4.40-4.47 (m, 1H), 4.53-4.61 (m, 1H), 6.79 (d,
1H), 7.20 (d, 1H), 7.73 (d, 1H), 7.76 (d, 1H), 7.77-7.81 (m, 1H),
7.89-7.91 (m, 1H), 8.10 (s, 1H).
Example 11
(S)--N-(1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-yl-
)-6-nitroimidazo[1,2-a]pyridine-2-carboxamide
The title compound was prepared using the procedure described in
Example 3(h) starting from
6-nitroimidazo[1,2-a]pyridine-2-carboxylic acid (0.551 mmol, 0.114
g) and
(S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-6-fluorobenzo-nitrile
(0.459 mmol, 0.128 g). DMF (4 ml) was used as the solvent and HBTU
(0.046 mmol, 0.017 g) was used instead of HOBt. The crude product
was purified by preparative HPLC. 0.0405 g of the title compound
was obtained. .sup.1H-NMR (400 MHz, MeOH-d.sub.4): .delta. 1.37 (d,
3H), 4.30-4.37 (m, 1H), 4.38-4.46 (m, 1H), 4.59-4.72 (m, 1H), 6.72
(d, 1H), 7.54 (d, 1H), 7.68 (d, 1H), 7.72 (s, 1H), 7.78 (d, 1H),
8.15-8.21 (m, 1H), 8.38 (s, 1H), 10.40-10.44 (m, 1H).
Example 12
(S)--N-(1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-yl-
)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxamide
The title compound was prepared using the procedure described in
Example 3(h) starting from
5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxylic acid (2.58
mmol, 428 mg) and
(S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-6-fluoro-benzonitrile
(1.717 mmol, 479 mg). DMF (10 ml) was used as the solvent. The
reaction mixture was diluted with water and extracted three times
with DCM. The combined organics were washed twice with water. The
organic phase was evaporated. The crude product was purified by
flash chromatography. 515 mg of the title compound was obtained.
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. 1.07 (d, 3H),
1.78-1.94 (m, 4H), 2.76 (t, 2H), 3.95 (t, 2H), 4.24-4.31 (m, 1H),
4.33-4.46 (m, 2H), 7.01 (d, 1H), 7.43 (s, 1H), 7.84 (d, 1H),
7.90-7.95 (m, 1H), 8.00 (s, 1H), 8.08 (d, 1H).
Example 13
(S)--N-(1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)-propan-2-y-
l)-1-isopropyl-2-methyl-1H-imidazole-4-carboxamide
a) Ethyl 1-isopropyl-2-methyl-1H-imidazole-4-carboxylate
Ethyl 2-methyl-1H-imidazole-4-carboxylate (0.649 mmol, 100 mg) and
KOH (0.973 mmol, 54.6 mg) were dissolved in DMF (2 ml) under
nitrogen atmosphere. 2-Iodopropane(isopropyliodide), stabilized
over copper (+98%, 0.973 mmol, 165 mg) was added and the resulting
mixture was stirred at RT overnight. NH.sub.4Cl solution was added
and the mixture was extracted three times with EtOAc. The combined
organics were washed with water, dried, filtered and evaporated.
The crude product was purified by flash chromatography. 83 mg of
the title compound was obtained. .sup.1H-NMR (400 MHz,
DMSO-d.sub.6): .delta. 1.25 (t, 3H), 1.36 (d, 6H), 2.32 (s, 3H),
4.18 (q, 2H), 4.31-4.43 (m, 1H), 7.87 (s, 1H).
b) 1-Isopropyl-2-methyl-1H-imidazole-4-carboxylic acid
Ethyl 1-isopropyl-2-methyl-1H-imidazole-4-carboxylate (0.423 mmol,
83 mg) was dissolved in methanol (0.5 ml) and THF (4 ml). NaOH 2 M
(2.115 mmol, 1.057 ml) was added and the resulting mixture was
stirred at RT overnight. The pH of the reaction mixture was
adjusted to about 5 with 1 M HCl and the mixture was evaporated.
Ethanol was added and the salt was removed by filtration. The salt
was flushed few times with ethanol. 51 mg of the title compound was
obtained. .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. 1.38 (d,
6H), 2.39 (s, 3H), 4.35-4.49 (m, 1H), 7.97 (s, 1H).
c)
(S)--N-(1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-
-yl)-1-isopropyl-2-methyl-1H-imidazole-4-carboxamide
The title compound was prepared using the procedure described in
Example 3(h) using 1-isopropyl-2-methyl-1H-imidazole-4-carboxylic
acid (0.303 mmol, 51 mg),
(S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-6-fluorobenzonitrile
(0.253 mmol, 70.4 mg) and only a catalytic amount of HOBt (0.025
mmol, 3.41 mg). DMF (2 ml) was used as the solvent in the reaction.
The work up was done by adding water to the reaction mixture and
extracting it three times with DCM. The combined organics were
washed twice with water. The organic phase was evaporated and the
residue was purified by flash chromatography. 86 mg of the title
compound was obtained. .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta.
1.06 (d, 3H), 1.34 (d, 6H), 2.35 (s, 3H), 4.23-4.47 (m, 4H), 7.02
(d, 1H), 7.62 (s, 1H), 7.86 (d, 1H), 7.90-7.96 (m, 1H), 8.00 (s,
1H), 8.04 (d, 1H).
Example 14
(S)--N-(1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-yl-
)-5-(2-hydroxypropan-2-yl)-1H-pyrazole-3-carboxamide
a) Ethyl 5-(2-hydroxypropan-2-yl)-1H-pyrazole-3-carboxylate
Zinc trifluoromethanesulfonate (2.378 mmol, 0.864 g),
2-methyl-3-butyn-2-ol (11.89 mmol, 1 g) and triethylamine (17.83
mmol, 1.804 g) were added into a flask under nitrogen atmosphere.
Ethyl diazoacetate (14.27 mmol, 1.628 g) was added slowly and the
temperature was carefully raised to 100.degree. C. and stirred for
8 h. Water was added and the mixture was extracted twice with DCM.
The combined DCM phases were dried, filtered and evaporated. The
crude product was purified by flash chromatography. 0.658 g of the
title compound was obtained. .sup.1H-NMR (400 MHz, DMSO-d.sub.6):
.delta. 1.28 (t, 3H), 1.45 (s, 6H), 4.24 (q, 2H), 5.34 (s, 1H),
6.52 (s, 1H), 13.22 (bs, 1H).
b) 5-(2-Hydroxypropan-2-yl)-1H-pyrazole-3-carboxylic acid
Ethyl 5-(2-hydroxypropan-2-yl)-1H-pyrazole-3-carboxylate (1.609
mmol, 0.319 g) was dissolved in ethanol (1 ml) and THF (4 ml). 2 M
NaOH (8.05 mmol, 4.02 ml) was added and the resulting mixture was
stirred overnight at RT. The reaction mixture was carefully
neutralized with HCl and evaporated. The residue was dissolved in a
small amount of ethanol and the salts were removed by filtration.
The filtrate was evaporated. 0.227 g of the title compound was
obtained. .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. 1.39 (s,
6H), 4.72 (bs, 1H), 6.24 (s, 1H), 12.20 (bs, 1H).
c)
(S)--N-(1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-
-yl)-5-(2-hydroxypropan-2-yl)-1H-pyrazole-3-carboxamide
The title compound was prepared using the procedure described in
Example 3(h) using
5-(2-hydroxypropan-2-yl)-1H-pyrazole-3-carboxylic acid (0.646 mmol,
110 mg) and
(S)-4-(1-(2-amino-propyl)-1H-pyrazol-3-yl)-2-chloro-6-fluorobenzo-nitrile
(0.539 mmol, 150 mg) and only a catalytic amount of HOBt (0.054
mmol, 7.28 mg). DMF was used as the solvent. Water was added to the
reaction mixture and the mixture was extracted it three times with
DCM. The combined organics were washed twice with water. The
organic phase was evaporated and the residue was purified by flash
chromatography and preparative HPLC, respectively. 45.4 mg of the
title compound was obtained. .sup.1H-NMR (400 MHz, DMSO-d.sub.6):
.delta. 1.13 (d, 3H), 1.43 (s, 6H), 4.17-4.55 (m, 3H), 5.27 (bs,
1H), 6.37 (bs, 1H), 6.99 (d, 1H), 7.82 (d, 1H), 7.86 (d, 1H), 7.97
(s, 1H), 8.08 (bs, 1H), 12.94 (bs, 1H).
Example 15
(S)--N-(1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)-propan-2-y-
l)-1-(2,2-difluoroethyl)-2-methyl-1H-imidazole-4-carboxamide
a) Ethyl
1-(2,2-difluoroethyl)-2-methyl-1H-imidazole-4-carboxylate
Ethyl 2-methyl-1H-imidazole-4-carboxylate (1.622 mmol, 250 mg) and
KOH (2.432 mmol, 136 mg) were suspended in DMF (2 ml).
1,1-Difluoro-2-iodoethane (4.86 mmol, 934 mg) was added and the
resulting mixture was stirred overnight at RT. During the stirring
additional 0.3 ml of 1,1-difluoro-2-iodoethane was added to
complete the reaction. Aqueous NH.sub.4Cl solution was added and
the mixture was extracted three times with EtOAc. The combined
organics were washed with water, dried, filtered and evaporated.
The crude product was purified by flash chromatography. 0.3 g of
the title compound was obtained. Two isomers were obtained in the
reaction and separated in later steps. Isomer 1: .sup.1H-NMR (400
MHz, DMSO-d.sub.6): .delta. 1.28 (t, 3H), 2.33 (s, 3H), 4.25 (q,
2H), 4.45-4.58 (m, 2H), 6.23-6.53 (m, 1H), 7.80 (s, 1H). Isomer 2:
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. 1.25 (t, 3H), 2.39 (s,
3H), 4.19 (q, 2H), 4.70-4.83 (m, 2H), 6.18-6.49 (m, 1H), 7.59 (s,
1H).
b) 1-(2,2-Difluoroethyl)-2-methyl-1H-imidazole-4-carboxylic
acid
Ethyl 1-(2,2-difluoroethyl)-2-methyl-1H-imidazole-4-carboxylate
(1.375 mmol, 300 mg) was dissolved in methanol (0.5 ml) and THF (4
ml). NaOH 2 M (4.12 mmol, 2.062 ml) was added and the resulting
mixture was stirred for 2.5 h at RT. The pH of the mixture was
adjusted to about 6 with 5 M HCl and the solvents were evaporated.
Ethanol was added and filtered. The filtrate was evaporated. 176 mg
of the title compound was obtained. The two isomers formed in the
previous reaction were still present. Isomer 1: .sup.1H-NMR (400
MHz, DMSO-d.sub.6): .delta. 2.25 (s, 3H), 4.67-4.80 (m, 2H),
6.09-6.44 (m, 1H), 6.94 (s, 1H). Isomer 2: .sup.1H-NMR (400 MHz,
DMSO-d.sub.6): .delta. 2.27 (s, 3H), 4.32-4.44 (m, 2H), 6.17-6.47
(m, 1H), 7.15 (s, 1H).
c)
(S)--N-(1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-
-yl)-1-(2,2-difluoroethyl)-2-methyl-1H-imidazole-4-carboxamide
The title compound was prepared using the procedure described in
Example 3(h) using
1-(2,2-difluoro-ethyl)-2-methyl-1H-imidazole-4-carboxylic acid
(0.926 mmol, 176 mg),
(S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-6-fluorobenzo-nitrile
(0.617 mmol, 172 mg) and only a catalytic amount of HOBt (0.062
mmol, 8.34 mg). DMF was used as the solvent. Water was added to the
reaction mixture and the mixture was extracted it three times with
DCM. The combined organics were washed twice with water. The
organic phase was evaporated and the residue was purified by flash
chromatography and preparative HPLC, respectively. 15.5 mg of the
title compound was obtained. .sup.1H-NMR (400 MHz, DMSO-d.sub.6):
.delta. 1.07 (d, 3H), 2.36 (s, 3H), 4.23-4.55 (m, 5H), 6.19-6.51
(m, 1H), 7.02 (d, 1H), 7.53 (s, 1H), 7.86 (d, 1H), 7.90-7.95 (m,
1H), 8.00 (s, 1H), 8.12 (d, 1H).
Example 16
N--((S)-1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)-propan-2-y-
l)-1-((R)-2-hydroxypropyl)-2-methyl-1H-imidazole-4-carboxamide
a) (R)-Ethyl
1-(2-hydroxypropyl)-2-methyl-1H-imidazole-4-carboxylate
Ethyl 2-methyl-1H-imidazole-4-carboxylate (3.24 mmol, 500 mg) and
potassium carbonate (32.4 mmol, 4482 mg) were dissolved in DMF (10
ml). (R)-(+)-propylene oxide (48.6 mmol, 3.41 ml) was added and the
resulting mixture was stirred at 60.degree. C. for 5.5 h. More
(R)-(+)-propylene oxide (1.5 ml) was added and the heating
continued for another hour. The mixture was evaporated and the
residue was purified by flash chromatography. 525 mg of the title
compound was obtained. .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta.
1.06 (d, 3H), 1.25 (t, 3H), 2.30 (s, 3H), 3.68-4.00 (m, 3H), 4.18
(q, 2H), 4.95 (d, 1H), 7.73 (s, 1H).
b) (R)-1-(2-Hydroxypropyl)-2-methyl-1H-imidazole-4-carboxylic
acid
(R)-Ethyl 1-(2-hydroxypropyl)-2-methyl-1H-imidazole-4-carboxylate
(2.474 mmol, 525 mg) was dissolved in methanol (1 ml) and THF (8
ml). NaOH 2 M (7.42 mmol, 3.71 ml) was added and the resulting
mixture was stirred overnight at RT. The pH of the mixture was
adjusted to about 5 with 1M HCl and the solvents were evaporated.
Ethanol was added and the salts were removed by filtration. The
filtrate was evaporated. 393 mg of the title compound was obtained.
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. 1.03 (m, 6H), 2.30 (s,
3H), 3.71-3.80 (m, 1H), 3.81-3.97 (m, 2H), 4.95 (bs), 7.67 (s,
1H).
c)
N--((S)-1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-
-yl)-1-((R)-2-hydroxypropyl)-2-methyl-1H-imidazole-4-carboxamide
The title compound was prepared using the procedure described in
Example 3(h) starting from
(R)-1-(2-hydroxypropyl)-2-methyl-1H-imidazole-4-carboxylic acid
(1.059 mmol, 195 mg) and
(S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-6-fluorobenzonitrile
(0.882 mmol, 246 mg) and using dry DMF (2 ml) as the solvent. After
the reaction was finished, DCM was added and the reaction mixture
was concentrated. The crude product was purified by flash
chromatography and preparative HPLC, respectively. 177.8 mg of the
title compound was obtained. .sup.1H-NMR (400 MHz, DMSO-d.sub.6):
.delta. 1.00-1.10 (m, 6H), 2.34 (s, 3H), 3.69-3.90 (m, 3H),
4.22-4.48 (m, 3H), 4.91 (d, 1H), 7.02 (d, 1H), 7.47 (s, 1H), 7.86
(d, 1H), 7.91-7.96 (m, 1H), 8.00 (s, 1H), 8.06 (d, 1H).
Example 17
(S)--N-(1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-yl-
)-1'-methyl-1'H-1,4'-bipyrazole-3-carboxamide
a) Methyl 1'-methyl-1'H-1,4'-bipyrazole-3-carboxylate
Into a solution of methyl 1H-pyrazole-3-carboxylate (10 g, 79.3
mmol) in DMF (80 ml), cuprous oxide (0.567 g, 3.96 mmol),
salicylaldoxime (1.08 g, 7.93 mmol), Cs.sub.2CO.sub.3 (64.4 g,
198.4 mmol) and 1-methyl-4-iodo pyrazole (16.5 g, 79.9 mmol) were
added and the mixture was stirred at 110.degree. C. for 48 h. The
reaction mixture was quenched with saturated solution of aqueous
NaHCO.sub.3 and extracted with EtOAc. The organic layer was
concentrated and purified by flash-chromatography. Yield 2.9 g.
1H-NMR (400 MHz; DMSO-d6): .delta. 3.83 (s, 3H), 3.88 (s, 3H), 7.90
(s, 1H), 8.29 (d, 2H). LC-MS: [M+H]=207.
b) 1'-Methyl-1'H-1,4'-bipyrazole-3-carboxylic acid
The title compound was prepared using the procedure described in
Example 33(c) starting from methyl
1'-methyl-1'H-1,4'-bipyrazole-3-carboxylate (2.9 g, 13.5 mmol).
Yield 1.4 g. 1H-NMR (400 MHz; DMSO-d6): .delta. 3.88 (s, 3H), 6.87
(d, 1H), 7.88 (s, 1H), 8.25 (d, 2H), 12.8 (bs, 1H). LC-MS:
[M+1]=193.19.
c)
(S)--N-(1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-
-yl)-1'-methyl-1'H-1,4'-bipyrazole-3-carboxamide
The title compound was prepared using the procedure described in
Example 3(h) starting from
1'-methyl-1'H-[1,4'-bipyrazole]-3-carboxylic acid (0.861 mmol, 165
mg) and
(S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-6-fluorobenzo-nitrile
(0.718 mmol, 200 mg) and using DMF (2 ml) as the solvent. DCM was
added and the reaction mixture was evaporated. The residue was
purified by flash chromatography. The purified product was
dissolved in DCM and washed three times with 1 M NaHCO.sub.3. The
combined organics were evaporated. 134 mg of the title compound was
obtained. .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. 1.15 (d,
3H), 3.88 (s, 3H), 4.28-4.42 (m, 2H), 4.42-4.52 (m, 1H), 6.75 (d,
1H), 7.01 (d, 1H), 7.81-7.88 (m, 3H), 7.94 (s, 1H), 8.13-8.17 (m,
2H), 8.18 (s, 1H).
Example 18
(S)--N-(1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-yl-
)-1H,2'H-3,3'-bipyrazole-5-carboxamide
a) Ethyl 1H,2'H-3,3'-bipyrazole-5-carboxylate
Pieces of sodium (0.26 g) were slowly added to ethanol (12 ml) with
stirring until all sodium had dissolved.
1-(1H-Pyrazol-5-yl)ethanone (8.61 mmol, 0.948 g) and diethyl
oxalate (8.61 mmol, 1.258 g) was added. The mixture was heated to
75.degree. C. for 3 h after which the stirring continued at RT
overnight. Hydrazine hydrochloride (8.61 mmol, 0.590 g) dissolved
in water (6 ml) was added. The resulting mixture was again heated
to 75.degree. C. for 3 h. The mixture was cooled to RT and
neutralized by adding 2 M NaOH. The mixture was extracted twice
with EtOAc and the combined organics were washed with water and
brine. The organic phase was dried, filtered and evaporated. The
crude product was purified by flash chromatography. 0.404 g of the
title compound was obtained. .sup.1H-NMR (400 MHz, MeOH-d.sub.4):
.delta. 1.39 (t, 3H), 4.38 (q, 2H), 6.69 (d, 1H), 7.10 (bs, 1H),
7.70 (bs, 1H).
b) 1H,2'H-3,3'-Bipyrazole-5-carboxylic acid
Ethyl 1H,2'H-3,3'-bipyrazole-5-carboxylate (1.959 mmol, 0.404 g)
was dissolved in ethanol (5 ml) and cooled in an ice bath. NaOH 1 M
solution (1.959 mmol, 4 ml) was slowly added. The solution was
heated to 60.degree. C. for 1 h. Ethanol was removed under vacuum
and the residue was diluted with tert-butyl methyl ether. The
solution was again cooled with an ice bath and acidified with 2 N
HCl solution. The solution was allowed to warm to ambient
temperature and stirred overnight. Water and DCM was added and the
phases were separated. Both phases were evaporated and combined.
0.551 g of the title compound was obtained. .sup.1H-NMR (400 MHz,
DMSO-d.sub.6): .delta. 6.70 (d, 1H), 7.04 (s, 1H), 7.77 (d,
1H).
c)
(S)--N-(1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-
-yl)-1H,2'H-3,3'-bipyrazole-5-carboxamide
The title compound was prepared using the procedure described in
Example 3(h) starting from 1H,2'H-3,3'-bipyrazole-5-carboxylic acid
(2.245 mmol, 0.4 g) and
(S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-6-fluorobenzonitrile
(1.871 mmol, 0.521 g) and using DMF (10 ml) as the solvent. Water
was added to the reaction mixture and the mixture was extracted
with EtOAc. The organic phase was washed with 2M Na.sub.2CO.sub.3,
water and brine. The organic phase was dried, filtered and
evaporated. The crude product was purified by flash chromatography
and preparative HPLC, respectively. 0.1277 g of the title compound
was obtained. .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. 1.19 (d,
3H), 4.27-4.56 (m, 3H), 6.64 (bs, 1H), 6.84 (bs, 1H), 6.98 (d, 1H),
7.77 (bs, 1H), 7.81-7.87 (m, 2H), 7.93-7.6 (m, 1H), 8.07 (br. s,
1H), 12.57-13.78 (m, 2H).
Example 19
N--((S)-1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)-propan-2-y-
l)-1-((S)-2-hydroxypropyl)-2-methyl-1H-imidazole-4-carboxamide
a) (S)-Ethyl
1-(2-hydroxypropyl)-2-methyl-1H-imidazole-4-carboxylate
Ethyl 2-methyl-1H-imidazole-4-carboxylate (1.622 mmol, 250 mg) and
potassium carbonate (16.22 mmol, 2241 mg) were dissolved in dry DMF
(5 ml) under nitrogen atmosphere. (S)-2-methyloxirane (24.32 mmol,
1.723 ml) was added and the resulting mixture was heated to
60.degree. C. and stirred for 5.5 h. More (S)-2-methyloxirane (1
ml) was added and the stirring continued at 60.degree. C. for one
additional hour. The solvent was evaporated. The crude product was
purified by flash chromatography. 139 mg of the title compound was
obtained. .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. 1.06 (d,
3H), 1.24 (t, 3H), 2.30 (s, 3H), 3.71-3.89 (m, 4H), 4.18 (q, 2H),
7.73 (s, 1H).
b) (S)-1-(2-Hydroxypropyl)-2-methyl-1H-imidazole-4-carboxylic
acid
(S)-Ethyl 1-(2-hydroxypropyl)-2-methyl-1H-imidazole-4-carboxylate
(0.655 mmol, 139 mg) was dissolved in methanol (0.5 ml) and THF (4
ml). NaOH 2 M (1.965 mmol, 0.982 ml) was added and the resulting
mixture was stirred overnight at RT. The mixture was acidified
(pH-5) with 1 M HCl and evaporated. Ethanol was added and the salts
were removed by filtration. The filtrate was evaporated. 112 mg of
the title compound was obtained. .sup.1H-NMR (400 MHz,
DMSO-d.sub.6): .delta. 1.06 (d, 3H), 2.30 (s, 3H), 3.70-3.91 (m,
4H), 7.59 (s, 1H).
b)
N--((S)-1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-
-yl)-1-((S)-2-hydroxypropyl)-2-methyl-1H-imidazole-4-carboxamide
The title compound was prepared using the procedure described in
Example 3(h) starting from
(S)-1-(2-hydroxypropyl)-2-methyl-1H-imidazole-4-carboxylic acid
(0.608 mmol, 112 mg) and
(S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-6-fluorobenzonitrile
(0.507 mmol, 141 mg) using DMF (2 ml) as the solvent. After the
reaction had stopped, DCM was added and the reaction mixture was
evaporated. The residue was purified by flash chromatography. The
purified product was dissolved in a mixture of MeOH/DCM and washed
twice with 1M NaHCO.sub.3. The organic phase was dried, filtered
and evaporated. The product was further purified by trituration
from diethyl ether, filtered and dried with vacuum. 31 mg of the
title compound was obtained. .sup.1H-NMR (400 MHz, DMSO-d.sub.6):
.delta. 1.01-1.08 (m, 6H), 2.33 (s, 3H), 3.68-3.91 (m, 3H),
4.22-4.48 (m, 3H), 4.91 (d, 1H), 7.02 (d, 1H), 7.47 (s, 1H), 7.86
(d, 1H), 7.94 (d, 1H), 8.01 (s, 1H), 8.06 (d, 1H).
Example 20
(S)--N-(1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-yl-
)-3,3'-bipyridine-6-carboxamide
a) tert-Butyl 5-bromopicolinate
5-Bromopicolinic acid (5 g, 24.8 mmol) was dissolved in t-BuOH (100
ml). To the solution, DMAP (0.303 g, 2.47 mmol), (Boc).sub.2O (8.1
g, 37.12 mmol) were added and stirred at 50.degree. C. overnight.
The solvent was concentrated under reduced pressure. The residue
was diluted with H.sub.2O and extracted with EtOAc. The organic
layer was concentrated. Yield 3.6 g. .sup.1H-NMR (400 MHz;
DMSO-d.sub.6): .delta. 1.55 (s, 9H), 7.92 (d, 1H), 8.23 (dd, 1H),
8.83 (d, 1H).
b) tert-Butyl 3,3'-bipyridine-6-carboxylate
Into a solution of tert-butyl 5-bromopicolinate (3.5 g, 13.56 mmol)
in DMF (40 ml) Pd(OAc).sub.2 (0.152 g, 0.68 mmol), dppf (0.753 g,
1.37 mmol), CuCl (1.4 g, 13.57 mmol), Cs.sub.2CO.sub.3 (8.9 g,
27.13 mmol) and pyridin-3-yl boronic acid (3.4 g, 27.13 mmol) were
added under inert atmosphere. The reaction mixture was stirred at
110.degree. C. overnight and diluted with H.sub.2O. The mixture was
filtered through a celite bed, and the filtrate was extracted with
EtOAc. The organic layer was concentrated. Yield 1.75 g.
.sup.1H-NMR (400 MHz; CDCl.sub.3): .delta. 1.67 (s, 9H), 7.43-7.47
(m, 1H), 7.91 (d, J=8.0 Hz, 1H), 8.01 (dd, 1H), 8.17 (d, 1H), 8.70
(dd, 1H), 8.88 (d, 1H), 8.97 (d, 1H).
c) 3,3'-Bipyridine-6-carboxylic acid
A solution of tert-butyl 3,3'-bipyridine-6-carboxylate (3.2 g, 12.5
mmol) in 4 M HCl in dioxane (100 ml) was stirred at 110.degree. C.
overnight. The reaction mixture was evaporated completely under
reduced pressure and triturated twice from diethyl ether. Yield 3.2
g. .sup.1H-NMR (400 MHz; D.sub.2O): .delta. 8.23-8.27 (m, 1H), 8.50
(d, 1H), 8.84 (d, 1H), 8.93 (d, 1H), 8.98 (d, 1H), 9.16 (s, 1H),
9.26 (s, 1H).
d)
(S)--N-(1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-
-yl)-3,3'-bipyridine-6-carboxamide
The title compound was prepared using the procedure described in
Example 3(h) starting from 3,3'-bipyridine-6-carboxylic acid (0.861
mmol, 172 mg) and
(S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-6-fluorobenzonitri-
le (0.718 mmol, 200 mg) using DMF (2 ml) as the solvent. After the
reaction had stopped, DCM was added and the reaction mixture was
evaporated. The residue was purified by flash chromatography and
trituration from methanol, respectively. 75 mg of the title
compound was obtained. .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta.
1.18 (d, 3H), 4.35-4.59 (m, 3H), 7.02 (d, 1H), 7.55-7.62 (m, 1H),
7.87-7.93 (m, 2H), 7.98 (s, 1H), 8.06-8.10 (m, 1H), 8.19-8.25 (m,
1H), 8.35 (dd, 1H), 8.68 (dd, 1H), 8.99-9.05 (m, 2H), 9.13 (d,
1H).
Example 21
(S)--N-(1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)-propan-2-y-
l)-6-(3,3-dimethylureido)imidazo[1,2-a]pyridine-2-carboxamide
a) Ethyl
6-(3,3-dimethylureido)imidazo[1,2-a]pyridine-2-carboxylate
Ethyl 6-aminoimidazo[1,2-a]pyridine-2-carboxylate (0.975 mmol, 0.2
g) was dissolved in THF (10 ml). Triethylamine (2.92 mmol, 0.296 g)
was added and the reaction mixture was cooled to 0.degree. C.
Dimethylcarbamyl chloride (1.462 mmol, 0.135 ml) was added
carefully and the mixture was allowed to warm to ambient
temperature with stirring. More of dimethylcarbamyl chloride (1.462
mmol, 0.135 ml) was added and the stirring continued for another
hour. The solvent was evaporated, DCM was added and the resulting
mixture was washed with NaHCO.sub.3 solution and water. The organic
phase was dried, filtered and evaporated. The crude product was
purified by flash chromatography. 0.066 g of the title compound was
obtained. .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. 1.31 (t,
3H), 2.95 (s, 6H), 4.29 (q, 2H), 7.39-7.44 (m, 1H), 7.50-7.54 (m,
1H), 8.41 (s, 1H), 8.54 (s, 1H), 8.89-8.93 (m, 1H).
b) 6-(3,3-Dimethylureido)imidazo[1,2-a]pyridine-2-carboxylic
acid
Ethyl 6-(3,3-dimethylureido)imidazo[1,2-a]pyridine-2-carboxylate
(0.239 mmol, 0.066 g) was dissolved in ethanol (5 ml). The solution
was cooled to 0.degree. C. and NaOH 2 M solution (0.478 mmol, 0.239
ml) was added. The resulting mixture was stirred at 0.degree. C.
Ethanol was evaporated and water was added. The pH of the water
phase was adjusted to .about.4 with HCl. The mixture was extracted
with EtOAc and the organic phase was dried, filtered and
evaporated. The residue was triturated with MeOH/DCM 1/9. The
filtered precipitate was dried under vacuum. 0.067 g of the title
compound was obtained. LC-MS: [M-1]=247.24.
c)
(S)--N-(1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-
-yl)-6-(3,3-dimethylureido)imidazo[1,2-a]pyridine-2-carboxamide
The title compound was prepared using the procedure described in
Example 3(h) starting from
6-(3,3-dimethylureido)imidazo[1,2-a]pyridine-2-carboxylic acid
(0.270 mmol, 0.067 g) and
(S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-6-fluorobenzonitrile
(0.108 mmol, 0.04 g) using DMF (4 ml) as the solvent. HBTU (0.027
mmol, 10.24 mg) was used instead of HOBt. The product precipitated
into the water phase and was separated by filtration. The organic
phase also contained the product. The organic phase was dried,
filtered and evaporated. The combined precipitates were purified by
preparative HPLC. 0.0192 g of the title compound was obtained.
.sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 1.13 (d, 3H), 2.95
(s, 6H), 4.30-4.54 (m, 3H), 7.01 (d, 1H), 7.40-7.45 (m, 1H),
7.47-7.52 (m, 1H), 7.87 (d, 1H), 7.93 (dd, 1H), 7.97 (s, 1H), 8.30
(s, 1H), 8.39 (bs, 1H), 8.49 (d, 1H), 8.87-8.91 (m, 1H).
Example 22
(S)--N-(1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)-propan-2-y-
l)-6-(methylsulfonamido)imidazo[1,2-a]pyridine-2-carboxamide
a) Ethyl
6-(N-(methylsulfonyl)methylsulfonamido)imidazo[1,2-a]pyridine-2-c-
arboxylate
Ethyl 6-aminoimidazo[1,2-a]pyridine-2-carboxylate (0.975 mmol, 0.2
g) was dissolved in THF (10 ml). Triethylamine (9.75 mmol, 0.986 g)
was added and the mixture was cooled to 0.degree. C.
Methanesulfonyl chloride (9.75 mmol, 1.116 g) was slowly added and
the mixture was allowed to cool to RT. The stirring continued at RT
until the reaction was finished. The solvent was evaporated, DCM
was added and washed with NaHCO.sub.3 solution and water. The
organic phase was dried, filtered and evaporated. The crude product
was purified with flash chromatography. 0.149 g of the title
compound was obtained. .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta.
1.33 (t, 3H), 3.61 (s, 6H), 4.34 (q, 2H), 7.50 (dd, 1H), 7.69-7.74
(m, 1H), 8.54-8.56 (m, 1H), 9.00-9.02 (m, 1H).
b) 6-(Methylsulfonamido)imidazo[1,2-a]pyridine-2-carboxylic
acid
Ethyl
6-(N-(methylsulfonyl)methylsulfonamido)imidazo[1,2-a]pyridine-2-car-
boxylate (0.412 mmol, 0.149 g) was dissolved in ethanol (10 ml) and
cooled to 0.degree. C. with an ice bath. NaOH 2 M solution (0.825
mmol, 0.412 ml) was added and stirred at 0.degree. C. for 3.5 h
after which the temperature was allowed to warm to RT. The stirring
continued overnight. The temperature was raised to 50.degree. C.
and stirred for 5 h. The mixture was again stirred at RT overnight.
Ethanol was evaporated and water was added. The pH was adjusted to
4 with 1 M HCl after which the product started to precipitate. The
precipitate was removed by filtration and dried under vacuum. 0.057
g of the title compound was obtained. .sup.1H-NMR (400 MHz,
DMSO-d.sub.6): .delta. 3.05 (s, 3H), 7.22-7.29 (m, 1H), 7.60-7.66
(m, 1H), 8.49-8.53 (m, 1H), 8.55 (s, 1H), 9.81 (s, 1H).
c)
(S)--N-(1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-
-yl)-6-(methylsulfonamido)imidazo[1,2-a]pyridine-2-carboxamide
The title compound was prepared using the procedure described in
Example 3(h) starting from
6-(methylsulfonamido)imidazo[1,2-a]pyridine-2-carboxylic acid
(0.215 mmol, 0.055 g) and
(S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-6-fluorobenzo-nitrile
(0.179 mmol, 0.050 g) using DCM (10 ml) as the solvent. HBTU (0.018
mmol, 6.80 mg) was used instead of HOBt. The mixture was diluted
with DCM and washed with Na.sub.2CO.sub.3 solution and water. The
organic phase was evaporated. The water phase and Na.sub.2CO.sub.3
phase were washed with EtOAc. The evaporated organic phases were
combined and purified by preparative HPLC. 0.0174 g of the title
compound was obtained. .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta.
1.14 (d, 3H), 3.04 (s, 3H), 4.27-4.58 (m, 3H), 7.00 (d, 1H), 7.27
(dd, 1H), 7.57-7.62 (m, 1H), 7.87 (d, 1H), 7.91 (dd, 1H), 7.95-7.97
(m, 1H), 8.36 (d, 1H), 8.49-8.51 (m, 1H), 8.55 (d, 1H), 9.77 (s,
1H).
Example 23
N--((S)-1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-yl-
)-5-(1-hydroxy-2-methylpropyl)isoxazole-3-carboxamide
a) Ethyl 5-(1-hydroxy-2-methylpropyl)isoxazole-3-carboxylate
Ethyl chlorooximidoacetate (6.79 mmol, 1.029 g) and
4-methyl-1-pentyn-3-ol (20.38 mmol, 2 g) were dissolved in toluene
(20 ml). Et.sub.3N (6.79 mmol, 0.947 ml) dissolved in toluene was
added dropwise. The mixture was stirred overnight at RT. The
mixture was diluted with EtOAc and washed with water. The organic
phase was dried, filtered and evaporated. The crude product was
purified by flash chromatography. 0.828 g of the title compound was
obtained. .sup.1H-NMR (400 MHz, MeOH-d.sub.4): .delta. 0.92 (d,
3H), 0.97 (d, 3H), 1.39 (t, 3H), 2.03-2.16 (m, 1H), 4.41 (q, 2H),
4.58 (d, 1H), 6.65 (s, 1H).
b) 5-(1-Hydroxy-2-methylpropyl)isoxazole-3-carboxylic acid
Ethyl 5-(1-hydroxy-2-methylpropyl)isoxazole-3-carboxylate (2.345
mmol, 0.5 g) was dissolved in ethanol (5 ml) and cooled to
0.degree. C. NaOH 1 M solution (5 ml) was slowly added and the
resulting mixture was allowed to warm to RT. The solution was
heated to 60.degree. C. for 3 h. Ethanol was removed by evaporation
and the residue was diluted with tert-butyl methyl ether. The
mixture was cooled to 0.degree. C. and acidified with 2 N HCl
solution. The mixture was allowed to warm to ambient temperature
and stirred overnight. The mixture was extracted with DCM. Both
organic and aqueous phases contained the product so both they were
combined and evaporated. 0.691 g of the title compound was
obtained. .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. 0.85 (d,
3H), 0.91 (d, 3H), 2.03 (qd, 1H), 4.54 (d, 1H), 6.66 (s, 1H).
c)
N--((S)-1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-
-yl)-5-(1-hydroxy-2-methylpropyl)isoxazole-3-carboxamide
The title compound was prepared using the procedure described in
Example 3(h) starting from
5-(1-hydroxy-2-methylpropyl)isoxazole-3-carboxylic acid (2.160
mmol, 0.4 g) and
(S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-6-fluoro-benzonitrile
(1.800 mmol, 0.502 g) using DMF (10 ml) as the solvent. The
reaction mixture was diluted with water and EtOAc, the phases were
separated and the organic phase was washed with 2 M
Na.sub.2CO.sub.3, water and brine. The organic phase was dried,
filtered and evaporated. The crude product was purified by flash
chromatography and preparative HPLC, respectively. 0.0146 g of the
title compound was obtained. .sup.1H-NMR (400 MHz, MeOH-d.sub.4):
.delta. 0.89 (d, 3H), 0.92-0.98 (m, 3H), 1.26 (d, 3H), 2.01-2.13
(m, 1H), 4.28-4.45 (m, 2H), 4.51-4.64 (m, 2H), 6.53 (d, 1H), 6.79
(d, 1H), 7.68-7.77 (m, 2H), 7.91 (s, 1H).
Example 24
(S)--N-(1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-yl-
)-5-(1,5-dimethyl-1H-pyrazol-3-yl)-1,2,4-oxadiazole-3-carboxamide
a) Ethyl
5-(1,5-dimethyl-1H-pyrazol-3-yl)-1,2,4-oxadiazole-3-carboxylate
Ethyl aminohydroxyiminoacetate (3.78 mmol, 0.5 g),
1,5-dimethyl-1H-pyrazole-3-carboxylic acid (95%, 3.78 mmol, 0.530
g) and 1,3-diisopropylcarbodiimide (4.16 mmol, 0.525 g) were
suspended in DCM (70 ml) under nitrogen atmosphere. The mixture was
stirred at RT for a day. The solvent was evaporated and pyridine
was added to the residue. The resulting mixture was refluxed for 6
h and stirred at RT overnight. Pyridine was evaporated and the
residue diluted with DCM and water. The phases were separated and
the water phase was extracted four times with DCM. The combined
organics were washed with aqueous HCl solution, saturated
NaHCO.sub.3, water and brine. The organic phase was dried, filtered
and evaporated. The crude product was purified by flash
chromatography. 0.285 g of the title compound was obtained.
.sup.1H-NMR (400 MHz, MeOH-d.sub.4): .delta. 1.43 (t, 3H), 2.30 (s,
3H), 4.23 (s, 3H), 4.49 (q, 2H), 6.96 (s, 1H).
b) 5-(1,5-Dimethyl-1H-pyrazol-3-yl)-1,2,4-oxadiazole-3-carboxylic
acid
Ethyl
5-(1,5-dimethyl-1H-pyrazol-3-yl)-1,2,4-oxadiazole-3-carboxylate
(1.206 mmol, 0.285 g) was dissolved in ethanol (7 ml) and cooled to
0.degree. C. with an ice bath. NaOH 1 M solution (3 ml) was added,
the ice bath was removed and the mixture was heated to 60.degree.
C. for 1.5 h. Ethanol was evaporated and the residue was diluted
with MTBE. The mixture was again cooled with an ice bath and
acidified with 2 M HCl. The mixture was warmed to RT and stirred
overnight. Water, MTBE and DCM were added, but the precipitate did
not dissolve. The organic phase and the water phase were combined
and evaporated. 0.336 g of the title compound was obtained.
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. 2.27 (s, 3H), 4.16 (s,
3H), 7.01 (s, 1H).
c)
(S)--N-(1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-
-yl)-5-(1,5-dimethyl-1H-pyrazol-3-yl)-1,2,4-oxadiazole-3-carboxamide
The title compound was prepared using the procedure described in
Example 3(h) starting from
5-(1,5-dimethyl-1H-pyrazol-3-yl)-1,2,4-oxadiazole-3-carboxylic acid
(1.614 mmol, 0.336 g) and
(S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-6-fluoro-benzonitrile
(1.345 mmol, 0.375 g) using DMF (10 ml) as the solvent. The
reaction mixture was diluted with water and EtOAc, the phases were
separated and the organic phase was washed with 2 M
Na.sub.2CO.sub.3, water and brine. The organic phase was dried,
filtered and evaporated. The crude product was purified by flash
chromatography and preparative HPLC, respectively. 0.003 g of the
title compound was obtained. .sup.1H-NMR (400 MHz, CDCl.sub.3):
.delta. 1.29 (d, 3H), 2.34 (s, 3H), 4.24 (s, 3H), 4.30 (dd, 1H),
4.49 (dd, 1H), 4.61-4.72 (m, 1H), 6.65 (d, 1H), 6.88 (s, 1H), 7.53
(d, 1H), 7.61 (dd, 1H), 7.78-7.82 (m, 1H), 8.01 (d, 1H).
Example 25
(S)--N-(1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-yl-
)-5-(isoxazol-3-yl)-1,2,4-oxadiazole-3-carboxamide
a) Ethyl 5-(isoxazol-3-yl)-1,2,4-oxadiazole-3-carboxylate
Ethyl aminohydroxyiminoacetate (3.78 mmol, 0.5 g),
3-isoxazolecarboxylic acid (3.78 mmol, 0.428 g) and
1,3-diisopropylcarbodiimide (4.16 mmol, 0.525 g) were dissolved in
DCM (70 ml) under nitrogen atmosphere. The mixture was stirred at
RT for a day. The solvent was evaporated to dryness and the residue
was dissolved in pyridine and refluxed for 6 h and overnight at RT.
Pyridine was evaporated and the residue was diluted with DCM and
water. The aqueous phase was extracted four times with DCM. The
combined organics were washed with aqueous HCl solution, saturated
NaHCO.sub.3, water and brine. The organic phase was dried, filtered
and evaporated. The crude product was purified by flash
chromatography. 0.396 g of the title compound was obtained.
Rotamers were obtained in .sup.1H-NMR and analysis was repeated at
elevated temperature. .sup.1H-NMR (400 MHz, DMSO-d.sub.6,
+60.degree. C.): .delta. 1.38 (t, 3H), 4.49 (q, 2H), 7.21 (d, 1H),
9.05 (d, 1H).
b) 5-(Isoxazol-3-yl)-1,2,4-oxadiazole-3-carboxylic acid
Ethyl 5-(isoxazol-3-yl)-1,2,4-oxadiazole-3-carboxylate (1.893 mmol,
0.396 g) was dissolved in ethanol (5 ml) and cooled to 0.degree. C.
with an ice bath. NaOH 1 M solution (4 ml) was slowly added and the
mixture was heated to 60.degree. C. for 3 h. Ethanol was evaporated
and the residue was diluted with MTBE. The mixture was cooled to
0.degree. C. and acidified by adding 2 M HCl. The mixture was
stirred at RT overnight. Water was added and the phases were
separated and the water phase was evaporated. 0.533 g of the title
compound was obtained. .sup.1H-NMR (400 MHz, D.sub.2O): .delta.
6.68 (d, 1H), 8.65 (d, 1H).
c)
(S)--N-(1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-
-yl)-5-(isoxazol-3-yl)-1,2,4-oxadiazole-3-carboxamide
The title compound was prepared using the procedure described in
Example 3(h) starting from
5-(isoxazol-3-yl)-1,2,4-oxadiazole-3-carboxylic acid (1.933 mmol,
0.35 g) and
(S)-4-(1-(2-amino-propyl)-1H-pyrazol-3-yl)-2-chloro-6-fluorobenzo-nitrile
(1.610 mmol, 0.449 g) using DMF (10 ml) as the solvent. The
reaction mixture was diluted with water and EtOAc, the phases were
separated and the organic phase was washed with 2M
Na.sub.2CO.sub.3, water and brine. The organic phase was dried,
filtered and evaporated. The crude product was purified by flash
chromatography and preparative HPLC, respectively. 0.0065 g of the
title compound was obtained. .sup.1H-NMR (400 MHz, CDCl.sub.3):
.delta. 1.26 (d, 3H), 4.28 (dd, 1H), 4.46 (dd, 1H), 4.56-4.66 (m,
1H), 6.63 (d, 1H), 6.82 (d, 1H), 7.51 (d, 1H), 7.64 (dd, 1H),
7.84-7.86 (m, 1H), 7.88 (d, 1H), 8.51 (d, 1H).
Example 26
(S)--N-(1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)-propan-2-y-
l)-3-(1H-imidazol-4-yl)-1H-pyrazole-5-carboxamide
a) Lithium
(Z)-4-(1-benzyl-1H-imidazol-4-yl)-1-ethoxy-1,4-dioxobut-2-en-2--
olate
5-Acetyl-1-benzylimidazole (24.97 mmol, 5 g) was dissolved in dry
diethyl ether (100 ml) under nitrogen atmosphere. The mixture was
cooled to -75.degree. C. and lithium bis(trimethylsilyl)amide (27.5
mmol, 27.5 ml) was added dropwise. The resulting mixture was
stirred at -75.degree. C. for an hour. Diethyl oxalate (32.5 mmol,
4.74 g) was added and the mixture was allowed to warm to ambient
temperature after which the mixture was stirred for a day at RT.
The formed precipitate was removed by filtration and the
precipitate was washed with diethyl ether. The precipitate was
dried under vacuum. 7.38 g of the title compound was obtained.
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. 1.22 (t, 3H), 4.11 (q,
2H), 5.61 (s, 2H), 6.17 (s, 1H), 7.15-7.31 (m, 5H), 7.48 (d, 1H),
7.88 (d, 1H).
b) Ethyl
3-(1-benzyl-1H-imidazol-4-yl)-1H-pyrazole-5-carboxylate
Lithium
(Z)-4-(1-benzyl-1H-imidazol-4-yl)-1-ethoxy-1,4-dioxobut-2-en-2-ol-
ate (9.80 mmol, 3.0 g) was suspended in dry ethanol (20 ml).
Hydrazine dihydro-chloride (12.74 mmol, 1.337 g) was added and the
resulting mixture was refluxed for 2 h. The mixture was cooled to
ambient temperature and evaporated. The sticky oil was purified by
trituration from ethanol. The precipitate was separated by
filtration and flushed with cold ethanol. 2.614 g of the title
compound was obtained. .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta.
1.31 (t, 3H), 4.33 (q, 2H), 5.81 (bs, 2H), 7.11-7.39 (m, 6H), 8.16
(bs, 1H), 9.31 (bs, 1H), 14.50 (bs, 1H).
c) Ethyl 3-(1H-imidazol-4-yl)-1H-pyrazole-5-carboxylate
Ethyl 3-(1-benzyl-1H-imidazol-4-yl)-1H-pyrazole-5-carboxylate (8.77
mmol, 2.6 g) was dissolved in a mixture of acetic acid (10 ml) and
ethanol (190 ml). The mixture was run through H-Cube (10% Pd/C
CatCart (8.77 mmol) flow 1.5 ml/min, +80.degree. C., Full hydrogen
mode). The collected fractions were combined and evaporated. The
acquired solid was stirred in toluene and evaporated. This was
repeated once more. 1.837 g of the title compound was obtained.
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. 1.33 (t, 3H), 4.35 (q,
2H), 7.38 (s, 1H), 8.07 (d, 1H), 9.14 (bs, 1H), 14.44 (bs, 1H).
LC-MS: [M-1]=205.0.
d) Ethyl
3-(1-trityl-1H-imidazol-4-yl)-1H-pyrazole-5-carboxylate
Ethyl 3-(1H-imidazol-4-yl)-1H-pyrazole-5-carboxylate (6.79 mmol,
1.4 g) was suspended in DCM (20 ml) under nitrogen atmosphere.
Triphenylmethyl chloride (8.15 mmol, 2.271 g) was added and stirred
for 10 min at RT. Triethylamine (8.15 mmol, 1.136 ml) was added and
the resulting mixture was stirred for 20 h at RT after which DCM
(10 ml) and triphenylmethyl chloride (1 g) was added. The stirring
was continued for another 4.5 days. More triphenylmethyl chloride
(1.14 g) and triethylamine (0.6 ml) was added and the mixture was
stirred for another day. The mixture was diluted with DCM and
washed with NaHCO.sub.3. The organic phase was dried, filtered and
evaporated. The residue was purified by trituration from ACN. 1.837
g of the title compound was obtained. .sup.1H-NMR (400 MHz,
DMSO-d.sub.6): .delta. 1.28 (t, 3H), 4.25 (q, 2H), 6.89 (s, 1H),
7.09-7.18 (m, 6H), 7.18-7.33 (m, 6H), 7.36-7.47 (m, 3H), 7.50 (s,
1H), 7.55 (s, 1H), 13.63 (bs, 1H).
e) 3-(1-Trityl-1H-imidazol-4-yl)-1H-pyrazole-5-carboxylic acid
Ethyl 3-(1-trityl-1H-imidazol-4-yl)-1H-pyrazole-5-carboxylate (4.01
mmol, 1.8 g) was dissolved in ethanol (20 ml) and cooled to
0.degree. C. NaOH 2 M solution (8.03 mmol, 4.01 ml) was added and
the mixture was stirred at RT for an hour. The mixture was heated
to 60.degree. C. and stirred for 10 h. Ethanol was evaporated and
the residue was diluted with water. The pH was adjusted to 4 with 1
M HCl solution which precipitated the product. The precipitate was
removed by filtration and washed with water. The solid was dried
under vacuum. 1.5 g of the title compound was obtained. .sup.1H-NMR
(400 MHz, DMSO-d.sub.6): .delta. 6.75 (bs, 1H), 7.08-7.17 (m, 6H),
7.18-7.34 (m, 5H), 7.36-7.49 (m, 8H). LC-MS: [M-1]=419.1.
f)
(S)--N-(1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-
-yl)-3-(1-trityl-1H-imidazol-4-yl)-1H-pyrazole-5-carboxamide
The title compound was prepared using the procedure described in
Example 3(h) starting from
3-(1-trityl-1H-imidazol-4-yl)-1H-pyrazole-5-carboxylic acid (0.875
mmol, 0.368 g) and
(S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-6-fluorobenzonitrile
(0.673 mmol, 0.250 g) using HBTU (0.067 mmol, 0.026 g) instead of
HOBt. DCM (4 ml) was used as the solvent. The reaction mixture was
diluted with DCM and washed with 1 M Na.sub.2CO.sub.3 and water.
The separated organic phase was dried, filtered and evaporated to
give 0.511 g of crude product. Another crude batch (931 mg) was
combined here and purified first by trituration in ACN and then by
flash chromatography to give 0.095 g of the product. .sup.1H-NMR
(400 MHz, DMSO-d.sub.6): .delta. 1.18 (d, 3H), 4.13-4.53 (m, 3H),
6.64 (s, 1H), 6.98 (d, 1H), 7.09-7.19 (m, 4H), 7.35-7.51 (m, 9H),
7.52-7.57 (m, 1H), 7.70-7.76 (m, 1H), 7.79-7.86 (m, 2H), 7.92 (s,
1H), 7.95 (s, 1H), 8.06-8.10 (m, 1H), 8.14-8.18 (m, 1H), 13.35 (bs,
1H).
g)
(S)--N-(1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-
-yl)-3-(1H-imidazol-4-yl)-1H-pyrazole-5-carboxamide
Into
(S)--N-(1-(3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propa-
n-2-yl)-3-(1-trityl-1H-imidazol-4-yl)-1H-pyrazole-5-carboxamide
(0.139 mmol, 0.095 g) was added 4 ml of a solution containing
formic acid (41.8 mmol, 1.926 g), THF (20 ml) and water (1 ml). The
resulting mixture was stirred first at RT after which the
temperature was raised to 50.degree. C. for 2 h. The solvent was
evaporated, ACN was added and evaporated again. This was repeated
once more. The crude product was purified by preparative HPLC.
0.0169 g of the title compound was obtained. .sup.1H-NMR (400 MHz,
CDCl.sub.3): .delta. 1.27 (d, 3H), 4.14 (dd, 1H), 4.45 (dd, 1H),
4-57-4.64 (m, 1H), 6.29 (bs), 6.63 (d, 1H), 6.90 (s, 1H), 7.32 (d,
1H), 7.51 (d, 1H), 7.52 (s, 1H), 7.63 (dd, 1H), 7.73 (d, 1H),
7.84-7.86 (m, 1H) LC-MS: [M+1]=439.0.
Example 27
(S)--N-(1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-yl-
)-2-(chloropropan-2-yl)oxazole-4-carboxamide
a)
(S)--N-(1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-
-yl)-2-(2-hydroxypropan-2-yl)oxazole-4-carboxamide
The title compound was prepared using the procedure described in
Example 3(h) starting from
2-(2-hydroxypropan-2-yl)oxazole-4-carboxylic acid (2.153 mmol,
0.368 g) and
(S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-6-fluorobenzo-nitrile
(2.153 mmol, 0.6 g) and using HBTU (0.215 mmol, 0.082 g) instead of
HOBt. DCM (15 ml) was used as the solvent. During the reaction a
new batch of starting materials was added to the reaction mixture.
The batch contained half the amount of starting materials used in
the beginning of the reaction with the exception that
(S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-6-fluorobenzonitrile
was not added at all. The resulting mixture was stirred for 2 days.
The mixture was diluted with DCM and washed with Na.sub.2CO.sub.3
solution and water. The organic phase was dried, filtered and
evaporated. The crude product was purified by flash chromatography.
0.669 g of the title compound was obtained. .sup.1H-NMR (400 MHz,
DMSO-d.sub.6): .delta. 1.13 (d, 3H), 1.52 (s, 6H), 4.27-4.54 (m,
3H), 5.63 (s, 1H), 7.02 (d, 1H), 7.83-7.89 (m, 2H), 7.98 (s, 1H),
8.10 (d, 1H), 8.48 (s, 1H).
b)
(S)--N-(1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-
-yl)-2-(chloropropan-2-yl)oxazole-4-carboxamide
(S)--N-(1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-y-
l)-2-(2-hydroxypropan-2-yl)oxazole-4-carboxamide (0.116 mmol, 0.05
g) was dissolved in DMF (5 ml) and triethylamine (0.255 mmol, 0.026
g) was added. Diethyl chlorophosphate (0.232 mmol, 0.040 g) was
carefully added with a syringe. The resulting mixture was stirred
at RT overnight. A mixture of ice and water was added and the
mixture was neutralized with 1 M NaOH. The mixture was extracted
twice with DCM. The combined organics were washed with water,
dried, filtered and evaporated. The crude product was purified by
preparative HPLC. 0.0047 g of the title compound was obtained.
.sup.1H-NMR (400 MHz, CDCl.sub.3): .delta. 1.26 (d, 3H), 2.04 (d,
6H), 4.29-4.36 (m, 1H), 4.38-4.46 (m, 1H), 4.54-4.66 (m, 1H), 6.64
(d, 1H), 7.39 (d, 1H), 7.51 (d, 1H), 7.61 (dd, 1H), 7.72-7.75 (m,
1H), 8.17 (s, 1H).
Example 28
(S)--N-(1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)-propan-2-y-
l)-2-(2-propen-2-yl)oxazole-4-carboxamide
The title product was a by-product from the reaction in which
(S)--N-(1-(3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-y-
l)-2-(chloro-propan-2-yl)oxazole-4-carboxamide was synthesized.
This compound was separated from the main product during
preparative HPLC purification. 0.008 g of the title compound was
obtained. .sup.1H-NMR (400 MHz, CDCl.sub.3): .delta. 1.27 (d, 3H),
2.13-2.18 (m, 3H), 4.31 dd, 1H), 4.42 (dd, 1H), 4.54-4.65 (m, 1H),
5.45-5.50 (m, 1H), 5.98-6.02 (m, 1H), 6.62 (d, 1H), 7.45 (d, 1H),
7.51 (d, 1H), 7.61 (dd, 1H), 7.71-7.74 (m, 1H), 8.11 (s, 1H).
Example 29
(S)--N-(1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-yl-
)-N-5-cyclopropylisoxazole-3,5-dicarboxamide
a) 3-(Ethoxycarbonyl)isoxazole-5-carboxylic acid
Ethyl chlorooximidoacetate (3.30 mmol, 0.5 g) and propiolic acid
(33.0 mmol, 2.311 g) were dissolved in diethyl ether (10 ml) with
stirring. Triethylamine (3.30 mmol, 0.334 g) dissolved in diethyl
ether (5 ml) was added dropwise to the previous mixture. The
reaction mixture was stirred for three days at RT during which more
triethylamine (2.times.0.668 g dissolved in 5 ml diethyl ether) was
added dropwise. The pH of the reaction mixture was adjusted to 2.
The organic phase was washed twice with water. The organic phase
was dried, filtered and evaporated. The residue was dried under
vacuum. 369 mg of the title compound was obtained. .sup.1H-NMR (400
MHz, CDCl.sub.3): .delta. 1.44 (t, 3H), 4.49 (q, 2H), 7.41 (s, 1H),
10.59 (bs, 1H).
b) Ethyl 5-(cyclopropylcarbamoyl)isoxazole-3-carboxylate
The title compound was prepared starting from
3-(ethoxycarbonyl)isoxazole-5-carboxylic acid (3.78 mmol, 0.7 g)
and cyclopropyl-amine (2.91 mmol, 0.166 g) using DCM (10 ml) as the
solvent. The mixture was diluted with DCM and washed with 1 M
Na.sub.2CO.sub.3 and water. The organic phase was dried, filtered
and evaporated. The crude product was purified by flash
chromatography. 0.284 g of the title compound was obtained.
.sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta. 0.58-0.64 (m, 2H),
0.70-0.77 (m, 2H), 1.33 (t, 3H), 2.80-2.90 (m, 1H), 4.38 (q, 2H),
7.39 (s, 1H), 9.04 (bs, 1H).
c) 5-(Cyclopropylcarbamoyl)isoxazole-3-carboxylic acid
Ethyl 5-(cyclopropylcarbamoyl)isoxazole-3-carboxylate (1.267 mmol,
0.284 g) was dissolved in ethanol (10 ml). The mixture was cooled
in an ice bath and NaOH 2 M solution (2.53 mmol, 1.267 ml) was
added. The resulting mixture was stirred in cold until the reaction
was complete. Ethanol was evaporated and water was added. The pH of
the mixture was adjusted to 4 with HCl. The precipitate was removed
by filtration. The filtrate was evaporated and purified by
trituration from 1/9 MeOH/DCM. 0.058 g of the title compound was
obtained. .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. 0.57-0.66
(m, 2H), 0.67-0.75 (m, 2H), 2.77-2.88 (m, 1H), 6.97 (s, 1H), 8.85
(m, 1H).
d)
(S)--N-3-(1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-
-2-yl)-N-5-cyclopropylisoxazole-3,5-dicarboxamide
The title compound was prepared using the procedure described in
Example 3(h) starting from
5-(cyclopropyl-carbamoyl)isoxazole-3-carboxylic acid (0.377 mmol,
0.074 g) and
(S)-4-(1-(2-amino-propyl)-1H-pyrazol-3-yl)-2-chloro-6-fluoro-benzonitrile
(0.377 mmol, 0.14 g) using DMF (4 ml) as the solvent. HBTU (0.038
mmol, 0.014 g) was used instead of HOBt. The crude product was
purified by preparative HPLC. 0.0011 g of the title compound was
obtained. .sup.1H-NMR (400 MHz, CDCl.sub.3): .delta. 0.69-0.75 (m,
2H), 0.91-0.98 (m, 2H), 1.26 (d, 3H), 2.87-2.96 (m, 1H), 4.26 (dd,
1H), 4.46 (dd, 1H), 4.55-4.65 (m, 1H), 6.58-6.63 (m, 1H), 6.64 (d,
1H), 7.30 (s, 1H), 7.51 (d, 1H), 7.63-7.69 (m, 1H), 7.82 (s, 1H),
7.93 (d, 1H).
Example 30
(S)-2-Bromo-N-(1-(3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)-pro-
pan-2-yl)-1H-imidazole-4-carboxamide
The title compound was prepared using the procedure described in
Example 3(h) starting from 2-bromo-1H-imidazole-4-carboxylic acid
(4.31 mmol, 0.822 g) and
(S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-6-fluorobenzonitrile
(3.59 mmol, 1 g) using DMF (10 ml) as the solvent. DCM and water
was added to the mixture, the layers were separated and the water
phase was extracted with DCM. The combined organics were washed
three times with water. The DCM phase was dried, filtered and
evaporated. The crude product was purified by flash chromatography
and preparative HPLC, respectively. 30.5 mg of the title compound
was obtained. .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. 1.10 (d,
3H), 4.24-4.49 (m, 3H), 7.00 (d, 1H), 7.62 (s, 1H), 7.83 (d, 1H),
7.87 (d, 1H), 7.96 (s, 1H), 8.11 (d, 1H), 13.23 (bs, 1H).
Example 31
(S)--N-(1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-yl-
)-1-(2-methylprop-1-enyl)-1H-pyrazole-3-carboxamide
a) Methyl 1-(2-methylprop-1-enyl)-1H-pyrazole-3-carboxylate
The title compound was prepared using the procedure described in
Example 17(a) starting from methyl 1H-pyrazole-3-carboxylate (8 g,
63.4 mmol) and 1-bromo-2-methyl propene (12.7 g, 95.2 mmol). The
product was purified with flash chromatography. Yield 2.4 g.
.sup.1H-NMR (400 MHz; CDCl.sub.3): .delta. 1.81 (d, 3H), 1.87 (d,
3H), 3.93 (s, 3H), 6.70 (d, 1H), 6.87 (d, 1H), 7.47 (d, 1H).
b) 1-(2-Methylprop-1-enyl)-1H-pyrazole-3-carboxylic acid
The title compound was prepared using the procedure described in
Example 32(d) starting from methyl
1-(2-methylprop-1-enyl)-1H-pyrazole-3-carboxylate (2.4 g, 13.3
mmol). Yield 1.6 g. .sup.1H-NMR (400 MHz; DMSO-d6): .delta. 1.84
(s, 6H), 6.77 (d, 1H), 6.82 (s, 1H), 7.87 (d, 1H), 12.7 (bs,
1H).
c)
(S)--N-(1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-
-yl)-1-(2-methylprop-1-enyl)-1H-pyrazole-3-carboxamide
The title compound was prepared using the procedure described in
Example 3(h) starting from
1-(2-methyl-prop-1-en-1-yl)-1H-pyrazole-3-carboxylic acid (1.076
mmol, 179 mg) and
(S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-6-fluoro-benzonitrile
(0.897 mmol, 250 mg) using DCM (5 ml) as the solvent. The mixture
was diluted with DCM, washed with 1M Na.sub.2CO.sub.3 and water.
The organic phase was dried, filtered and evaporated. The product
was purified by flash chromatography. 298 mg of the title compound
was obtained. .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. 1.12 (d,
3H), 1.80 (d, 3H), 1.84 (d, 3H), 4.27-4.50 (m, 3H), 6.66 (d, 1H),
6.77-6.80 (m, 1H), 7.01 (d, 1H), 7.83 (d, 1H), 7.85-7.89 (m, 2H),
7.95-7.98 (m, 1H), 8.15 (d, 1H).
Example 32
(S)--N-(1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-yl-
)-1-cyclopropyl-1H-pyrazole-3-carboxamide
a) 1H-Pyrazole-3-carboxylic acid
3-Methylpyrazole (20 g, 243.5 mmol) was dissolved in water (500
ml). Into the solution, aqueous KMnO.sub.4 (96.2 g, 608.9 mmol in
900 ml of water) was added and the resulting mixture was refluxed
for 12 h. The reaction mixture was filtered through a celite bed
and concentrated. The white residue was dissolved in water and made
to pH 2 using concentrated HCl. The precipitated solids were
filtered under vacuum. Yield 15 g. LC-MS: [M+1]=112.98.
b) Methyl 1H-pyrazole-3-carboxylate
1H-Pyrazole-3-carboxylic acid (15 g, 133.8 mmol) was dissolved in
MeOH (250 ml). Concentrated H.sub.2SO.sub.4 (30 ml) was added to
the solution. The resulting mixture was refluxed for 12 h and
concentrated. The residue obtained was quenched by saturated
aqueous solution of NaHCO.sub.3 and extracted with EtOAc. The
organic layer was concentrated. Yield 12.05 g. .sup.1H-NMR (400
MHz; CDCl.sub.3): .delta. 3.98 (s, 3H), 6.86 (d, 1H), 7.85 (d, 1H),
11.9 (bs, 1H).
c) Methyl 1-cyclopropyl-1H-pyrazole-3-carboxylate
Methyl 1H-pyrazole-3-carboxylate (4 g, 31.7 mmol) was dissolved in
dichloroethane (160 ml). Na.sub.2CO.sub.3 (6.72 g, 63.4 mmol) and
cyclopropylboronic acid (5.44 g, 63.4 mmol) were added to the
solution. The resulting mixture was heated to 70.degree. C. and a
hot solution of bipyridine (4.92 g, 31.6 mmol) and Cu(OAc).sub.2
(5.72 g, 31.6 mmol) in dichloroethane (40 ml) was added. The
mixture was stirred at 70.degree. C. under an oxygen atmosphere
overnight. Saturated aqueous solution of NaHCO.sub.3 was added to
the reaction mixture and extracted with EtOAc. The organic layer
was evaporated and the residue was purified by flash
chromatography. Yield 2.5 g. .sup.1H-NMR (400 MHz; DMSO-d6):
.delta. 1.04-1.09 (m, 2H), 1.17-1.23 (m, 2H), 3.64-3.69 (m, 1H),
3.91 (s, 3H), 6.78 (d, 1H), 7.46 (d, 1H).
d) 1-Cyclopropyl-1H-pyrazole-3-carboxylic acid
Methyl 1-cyclopropyl-1H-pyrazole-3-carboxylate (2.5 g, 15 mmol) was
dissolved in THF (40 ml) and H.sub.2O (10 ml). LiOH.H.sub.2O (1.50
g, 22.5 mmol) was added and the mixture was stirred at RT
overnight. The reaction mixture was concentrated and acidified to
pH 2 using 1 N HCl. The mixture was extracted with EtOAc and the
organic layer was concentrated. Yield 1.6 g. .sup.1H-NMR (400 MHz;
DMSO-d6): .delta. 0.96-1.02 (m, 2H), 1.04-1.09 (m, 2H), 3.79-3.84
(m, 1H), 6.66 (d, 1H), 7.88 (d, 1H), 12.6 (bs, 1H).
e)
(S)--N-(1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-
-yl)-1-cyclopropyl-1H-pyrazole-3-carboxamide
1-Cyclopropyl-1H-pyrazole-3-carboxylic acid (0.30 g, 1.29 mmol) was
dissolved in DCM (20 ml). EDCI (0.692 g, 3.61 mmol), HOBt (0.487 g,
3.61 mmol) and DIPEA (0.932 g, 7.22 mmol) were added at 0.degree.
C. to the solution. The resulting mixture was stirred at 0.degree.
C. for 15 min.
(S)-4-(1-(2-Aminopropyl)-1H-pyrazol-3-yl)-2-chloro-6-fluorobenzonitrile
(0.502 g, 1.8 mmol) dissolved in DCM (2 ml) was added and the
mixture was stirred overnight. The reaction mixture was quenched by
the addition of water and extracted with DCM. The organic layer was
evaporated and the residue was purified by flash chromatography.
Yield: 400 mg. .sup.1H-NMR (400 MHz; DMSO-d6): .delta. 0.97-1.17
(m, 7H), 3.74-3.80 (m, 1H), 4.26-4.41 (m, 3H), 6.53 (d, 1H), 7.01
(d, 1H), 7.82-7.87 (m, 3H), 7.96 (s, 1H), 8.14 (d, 1H).
Example 33
N--((S)-1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-yl-
)-2-(1-hydroxyethyl)-1H-imidazole-4-carboxamide
a) Methyl
2-(1-ethoxyvinyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidaz-
ole-4-carboxylate
Methyl-2-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carbox-
ylate (10 g, 29.9 mmol) was dissolved in dioxane (200 ml).
Tributyl(1-ethoxy-vinyl)stannane (16.2 g, 44.8 mmol) was added to
the solution. The resulting mixture was degassed and purged with
argon for 20 min. Then Pd(PPh.sub.3).sub.4 (3.45 g, 2.99 mmol) was
added and the mixture was refluxed overnight. The reaction mixture
was cooled to RT and diluted with cold water. The mixture was
extracted with EtOAc and washed with aqueous KF solution. The
organic layer was concentrated to give the desired product. Yield
12.1 g. LC-MS: [M+1]=327.78.
b) Methyl
2-acetyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-car-
boxylate
Into a flask containing a solution of
methyl-2-(1-ethoxyvinyl)-1-((2-(tri-methylsilyl)-ethoxy)methyl)-1H-imidaz-
ole-4-carboxylate (3.5 g, 10.7 mmol) in THF (25 ml), 2 N HCl (25
ml) was added at RT and stirred for 3 h. The reaction mixture was
concentrated and extracted with DCM. The organic layer was
evaporated and the residue was purified by flash chromatography.
Yield 2.6 g. .sup.1H-NMR (400 MHz; CDCl.sub.3): .delta. -0.016 (s,
9H), 0.94 (t, 2H), 2.73 (s, 3H), 3.58 (t, 2H), 3.94 (s, 3H), 5.76
(s, 2H), 7.93 (s, 1H).
c)
2-Acetyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carboxylic
acid
The title compound was prepared using the procedure described in
Example 32(d) starting from
methyl-2-acetyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carbo-
xylate (2.5 g, 8.3 mmol). Yield 2 g. .sup.1H-NMR (400 MHz;
DMSO-d.sub.6): .delta. -0.06 (s, 9H), 0.83 (t, 2H), 2.57 (s, 3H),
3.53 (t, 2H), 5.68 (s, 2H), 8.23 (s, 1H), 12.76 (s, 1H).
d)
(S)-2-Acetyl-N-(1-(3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)-
-propan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carboxam-
ide
The title compound was prepared using the procedure described in
Example 32(e) starting from
2-acetyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carboxylic
acid (400 mg, 1.4 mmol) and
(S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-6-fluoro-benzonitrile
(389 mg, 1.4 mmol). The product was purified with flash
chromatography. Yield 260 mg. .sup.1H-NMR (400 MHz; DMSO-d.sub.6):
.delta. -0.09 (s, 9H), 0.81 (t, 2H), 1.15 (d, 3H), 2.61 (s, 3H),
3.48 (t, 2H), 4.33-4.48 (m, 3H), 5.66 (s, 2H), 7.02 (d, 1H),
7.84-7.87 (m, 2H), 7.95 (s, 1H), 8.06 (s, 1H), 8.15 (d, 1H).
e)
N--((S)-1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-
-yl)-2-(1-hydroxyethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole--
4-carboxamide
(S)-2-Acetyl-N-(1-(3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)-p-
ropan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carboxamid-
e (290 mg, 0.53 mmol) was dissolved in MeOH (20 ml). NaBH.sub.4 (30
mg, 0.79 mmol) was added to the solution in portions at 0.degree.
C. and the mixture was stirred at RT for 3 h. The reaction mixture
was concentrated and dluted with water. The mixture was extracted
with DCM and the organic layer was concentrated. The product was
purified by column chromatography. Yield 245 mg. .sup.1H-NMR (400
MHz; DMSO-d.sub.6): .delta. -0.05 (s, 9H), 0.81-0.86 (m, 2H),
1.07-1.1 (m, 3H), 1.49 (d, 3H), 3.47-3.51 (m, 2H), 4.29-4.43 (m,
3H), 4.88-4.91 (m, 1H), 5.4-5.45 (m, 3H), 7.03 (d, 1H), 7.68 (d,
1H), 7.86-8.00 (m, 4H).
f)
N--((S)-1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-
-yl)-2-(1-hydroxyethyl)-1H-imidazole-4-carboxamide
The title compound was prepared using the procedure described in
Example 52(h) starting from
N--((S)-1-(3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-y-
l)-2-(1-hydroxyethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4--
carboxamide (0.65 g, 1.2 mmol). Yield 124 mg. .sup.1H-NMR (400 MHz;
DMSO-d.sub.6): .delta. 1.07 (d, 3H), 1.41 (d, 3H), 4.27-4.41 (m,
3H), 4.73-4.78 (m, 1H), 5.51 (d, 1H), 7.03 (d, 1H), 7.41 (s, 1H),
7.86 (d, 1H), 7.92 (d, 1H), 8.01 (d, 2H), 12.28 (s, 1H).
Example 34
(S)-2-acetyl-N-(1-(3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)-pr-
opan-2-yl)-1H-imidazole-4-carboxamide
a)
(S)-2-Acetyl-N-(1-(3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)-
propan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carboxami-
de
The title compound was prepared using the procedure described in
Example 32(e) starting from starting from
2-acetyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carboxylic
acid (400 mg, 1.4 mmol) and
(S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-6-fluorobenzonitrile
(389 mg, 1.4 mmol). The product was purified with
flash-chromatography. Yield: 260 mg. .sup.1H-NMR (400 MHz;
DMSO-d.sub.6): .delta. -0.09 (s, 9H), 0.81 (t, 2H), 1.15 (d, 3H),
2.61 (s, 3H), 3.48 (t, 2H), 4.33-4.48 (m, 3H), 5.66 (s, 2H), 7.02
(d, 1H), 7.84-7.87 (m, 2H), 7.95 (s, 1H), 8.06 (s, 1H), 8.15 (d,
1H).
b)
(S)-2-Acetyl-N-(1-(3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)-
propan-2-yl)-1H-imidazole-4-carboxamide
The title compound was prepared using the procedure described in
Example 52(h) starting from
(S)-2-acetyl-N-(1-(3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)pr-
opan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carboxamide
(250 mg, 0.45 mmol). Yield 124 mg. .sup.1H-NMR (400 MHz;
DMSO-d.sub.6): .delta. 1.14 (d, 3H), 2.57 (s, 3H), 4.31-4.5 (m,
3H), 7.02 (d, 1H), 7.78 (d, 1H), 7.84-7.87 (m, 2H), 7.94 (s, 1H),
8.11 (d, 1H), 13.62 (s, 1H).
Example 35
(S)--N-(1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-yl-
)-2-(2-hydroxypropan-2-yl)-1H-imidazole-4-carboxamide
a) Methyl
2-(2-hydroxypropan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-
-imidazole-4-carboxylate
The title compound was prepared using the procedure described in
Example 2(d) starting from methyl
2-acetyl-1-((2-(trimethylsilyl)-ethoxy)methyl)-1H-imidazole-4-carboxylate
(3 g, 10 mmol). The product was purified by flash-chromatography.
Yield 1.5 g. .sup.1H-NMR (400 MHz; DMSO-d.sub.6): .delta. -0.03 (s,
9H), 0.86 (t, 2H), 1.52 (s, 6H), 3.56 (t, 2H), 3.73 (s, 3H), 5.64
(s, 2H), 7.94 (s, 1H).
b)
2-(2-Hydroxypropan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidaz-
ole-4-carboxylic acid
The title compound was prepared using the procedure described in
Example 32(d) starting from methyl
2-(2-hydroxypropan-2-yl)-1-((2-(trimethylsilyl)ethoxy)-methyl)-1H-imidazo-
le-4-carboxylate (1.5 g, 4.7 mmol). Yield 1 g. .sup.1H-NMR (400
MHz; DMSO-d.sub.6): .delta. -0.02 (s, 9H), 0.86 (t, 2H), 1.52 (s,
6H), 3.56 (t, 2H), 5.44 (s, 1H), 5.62 (s, 2H), 7.83 (s, 1H).
c)
(S)--N-(1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-
-yl)-2-(2-hydroxypropan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imid-
azole-4-carboxamide
The title compound was prepared using the procedure described in
Example 32(e) starting from
2-(2-hydroxypropan-2-yl)-1-((2-(trimethylsilyl)ethoxy)-methyl)-1H-imidazo-
le-4-carboxylic acid (400 mg, 1.33 mmol) and
(S)-4-(1-(2-amino-propyl)-1H-pyrazol-3-yl)-2-chloro-6-fluorobenzonitrile
(370 mg, 1.33 mmol). The product was purified with
flash-chromatography. Yield 305 mg. LC-MS: [M+1]=561.17.
d)
(S)--N-(1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-
-yl)-2-(2-hydroxypropan-2-yl)-1H-imidazole-4-carboxamide
The title compound was prepared using the procedure described in
Example 52(h) starting from
(S)--N-(1-(3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-y-
l)-2-(2-hydroxy-propan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imida-
zole-4-carboxamide (370 mg, 0.66 mmol). Yield 136 mg. .sup.1H-NMR
(400 MHz; DMSO-d.sub.6): .delta. 1.09 (d, 3H), 1.46 (s, 6H),
4.28-4.42 (m, 3H), 5.35 (s, 1H), 7.04 (d, 1H), 7.38 (d, 1H),
7.75-7.99 (m, 4H), 12.15 (s, 1H).
Example 36
(S)--N-(1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)-propan-2-y-
l)-2-cyclopropyl-1-methyl-1H-imidazole-4-carboxamide
The title compound was prepared using the procedure described in
Example 32(e) starting from
2-cyclopropyl-1-methyl-1H-imidazole-4-carboxylic acid (260 mg, 1.56
mmol) and
(S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-6-fluorobenzo-nitrile
(435 mg, 1.56 mmol). Yield 123 mg. .sup.1H-NMR (400 MHz;
DMSO-d.sub.6): .delta. 0.81-0.91 (m, 4H), 1.08 (d, 3H), 1.95 (m,
1H), 3.65 (s, 3H), 4.27-4.38 (m, 3H), 7.01 (s, 1H), 7.46 (s, 1H),
7.69 (d, 1H), 7.87 (d, 2H), 7.96 (s, 1H).
Example 37
(S)--N.sup.4-(1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propa-
n-2-yl)-1H-imidazole-2,4-dicarboxamide
a) Methyl
2-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carb-
oxylate
Into a flask containing a solution of methyl
2-formyl-1-((2-(trimethylsilyl)-ethoxy)-methyl)-1H-imidazole-4-carboxylat-
e (9 g, 31.6 mmol) in MeOH (200 ml), 50% aqueous NH.sub.2OH.HCl
solution (2.5 ml) was added and stirred at RT for 3 h. The reaction
mixture was concentrated and extracted with EtOAc. The organic
layer was concentrated and the resulting residue was dissolved in
DCM (200 ml). Pyridine (12 ml) and trifluoroacetic anhydride (18
ml) were added to the above mixture and stirred for 12 h. The
reaction mixture was quenched with aqueous NaHCO.sub.3 solution and
extracted with DCM. The organic layer was concentrated and purified
with flash chromatography. Yield 4.1 g. .sup.1H-NMR (400 MHz;
DMSO-d.sub.6): .delta. -0.04 (s, 9H), 0.87 (t, 2H), 3.56 (t, 2H),
3.81 (s, 3H), 5.29 (s, 2H), 8.28 (s, 1H).
b)
2-Carbamoyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carboxy-
lic acid
Methyl
2-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carbox-
ylate (3 g, 10.7 mmol) was dissolved in THF (30 ml) and H.sub.2O (8
ml). LiOH.H.sub.2O (1.1 g, 16.1 mmol) was added to the solution and
the mixture was stirred at RT overnight. The reaction mixture was
concentrated and acidified to pH 2 using 1 N HCl. The mixture was
extracted with EtOAc and the organic layer was concentrated. Yield
2.2 g. .sup.1H-NMR (400 MHz; DMSO-d.sub.6): .delta. -0.06 (s, 9H),
0.85 (t, 2H), 2.57 (s, 3H), 3.52 (t, 2H), 5.79 (s, 2H), 7.66 (s,
1H), 7.96 (s, 1H), 8.09 (s, 1H), 12.68 (s, 1H).
c)
(S)--N.sup.4-(1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)pr-
opan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-2,4-dicarboxa-
mide
The title compound was prepared using the procedure described in
Example 32(e) starting from
2-carbamoyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carboxyli-
c acid (500 mg, 1.7 mmol) and
(S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-6-fluorobenzonitrile
(472 mg, 1.7 mmol). The product was purified with
flash-chromatography. Yield 420 mg. LC-MS: [M+1]=546.19.
d)
(S)--N.sup.4-(1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)pr-
opan-2-yl)-1H-imidazole-2,4-dicarboxamide
The title compound was prepared using the procedure described in
Example 52(h) starting from
(S)--N.sup.4-(1-(3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)prop-
an-2-yl)-1-((2-(trimethylsilyl)ethoxy)-methyl)-1H-imidazole-2,4-dicarboxam-
ide (0.45 g, 0.82 mmol) Yield 310 mg. .sup.1H-NMR (400 MHz;
DMSO-d.sub.6): .delta. 1.14 (d, 3H), 4.28-4.24 (m, 3H), 7.01 (s,
1H), 7.63-7.67 (m, 3H), 7.84-7.94 (m, 4H), 13.39 (s, 1H).
Example 38
4-(1-(3-((S)-1-(3-(3-Chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl-car-
bamoyl)-1H-pyrazol-5-yl)ethoxy)-4-oxobutanoic acid
a)
2-Chloro-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)benzonitrile
4-Bromo-2-chlorobenzonitrile (30 g, 139 mmol), 90 ml of THF and 360
ml of toluene were placed in reaction vessel under nitrogen
atmosphere. Bis(triphenylphosphine)-palladium(II) chloride (4.57 g,
6.51 mmol), Na.sub.2CO.sub.3 (33.1 g, 312 mmol), 180 ml of water
and tetrabutylammonium bromide (0.894 g, 2.77 mmol) were added. The
reaction mixture was heated up to 42.degree. C.
1-(Tetrahydro-2H-pyran-2-yl)-1H-pyrazole-5-boronic acid pinacol
ester (42.4 g; 152 mmol) was added in three portions within one
hour. The reaction was agitated at 42.degree. C. for one hour
followed with addition of 180 ml of water and cool down. The
reaction mixture was filtered and layers separated. Organic phase
was washed with 400 ml of water. The layers were separated and the
toluene phase was distilled close to dryness. 180 ml of ethanol was
added to the warm residue and the mixture was cooled down to
5.degree. C. for three hours. The precipitate was filtered and
washed with cold ethanol. 36.4 g of the title compound was obtained
after vacuum drying. .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta.
1.48-1.70 (m, 3H), 1.78-1.86 (m, 1H), 1.90-2.00 (m, 1H), 2.29-2.46
(m, 1H), 3.55-3.68 (m, 1H), 3.93-4.04 (m, 1H), 5.29 (dd, 1H), 6.72
(d, 1H), 7.65 (d, 1H), 7.72 (dd, 1H), 7.92 (d, 1H), 8.13 (d,
1H).
b) 2-Chloro-4-(1H-pyrazol-3-yl)benzonitrile hydrochloride
HCl/EtOH .about.10% (35.1 ml, 115 mmol) was set into the reaction
flask under nitrogen atmosphere.
2-Chloro-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)-benzonitrile
(12 g, 46.2 mmol) was added. The mixture was cooled to 10.degree.
C. and agitated for 2 h. Temperature was set to 0.degree. C. and
the mixture was stirred additional 2 hours. The precipitation was
filtered, washed with ethanol and dried under vacuum overnight to
obtain 9.24 g of the title compound. .sup.1H-NMR (400 MHz,
DMSO-d.sub.6): .delta. 6.99 (d, 3H), 7.86 (d, 1H), 7.96-8.02 (m,
2H), 8.14-8.17 (m, 1H).
c) 2-Chloro-4-(1H-pyrazol-3-yl)benzonitrile
2-Chloro-4-(1H-pyrazol-5-yl)benzonitrile hydrochloride (8 g, 33.3
mmol) was charged to the reaction flask and methanol (74 ml),
activated charcoal (0.36 g) and celite (0.46 g) were added. The
reaction mixture was refluxed for 1 h, filtered, and the solid was
washed with warm methanol. A half of the methanol was distilled out
and water (40 ml) was added at 55.degree. C. slowly. 50% NaOH
solution (1.916 ml, 36.7 mmol) was added slowly, the mixture was
stirred for 10 min and cooled to RT. MeOH was evaporated and
residue cooled to RT. Water (49 ml) was added and the precipitate
was filtered and washed with water and dried under vacuum overnight
at 60.degree. C. to obtain 6.21 g of the title compound.
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. 6.99 (d, 1H), 7.86 (d,
1H), 7.96-8.01 (m, 2H), 8.24-8.16 (m, 1H).
d)
(S)-4-(1-(2-Aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile
2-Chloro-4-(1H-pyrazol-3-yl)benzonitrile (30 g, 145 mmol),
(S)-tert-butyl-1-hydroxypropan-2-ylcarbamate (51.4 g, 291 mmol),
triphenylphosphine (77 g, 291 mmol) and 210 ml of EtOAc were place
in to the reaction vessel under nitrogen atmosphere and stirred for
15 min. DIAD (57.8 ml, 291 mmol) was added slowly in 1.5 h at RT
keeping the temperature stable and the reaction was stirred
overnight at RT. Concentrated HCl (134 ml, 1453 mmol) was added and
the mixture was stirred at RT overnight. Water (165 ml) and DCM
(240 ml) were added, the mixture was stirred for 30 min and layers
were separated. Organic phase was washed with 2.times.270 ml of
acidic water (pH.about.1). Water phases were combined and washed
with 2.times.120 ml of dichloromethane. Dichloromethane (150 ml)
was added, pH set to 11.5 by 50% NaOH and the mixture was stirred
for 75 min. The solution was filtered through the celite, layers
were separated and organic phase was washed with 171 ml of water.
DCM was distilled out at 33.degree. C. under reduced pressure and
60 ml of heptanes was added. Precipitation was started, 60 ml of
heptane added and the mixture was stirred overnight. Some DCM was
evaporated, 60 ml heptanes was added and the mixture was cooled to
10.degree. C. The precipitate was filtered, washed with 20 ml of
IPA:heptane (10:90) and dried under vacuum to obtain 24.55 g of the
title compound. .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. 1.03
(d, 3H), 3.34-3.43 (d, 2H), 4.14 (d, 2H), 6.99 (d, 1H), 7.89 (d,
1H), 7.96 (dd, 1H), 7.99 (dd, 1H), 8.12-8.14 (m, 1H).
e)
(S)-5-Acetyl-N-(1-(3-(3-Chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2--
yl)-1H-pyrazole-3-carboxamide
3-Acetyl-1H-pyrazole-5-carboxylic acid (10.20 g, 66.2 mmol), DCM
(195 ml) and DIPEA (11.52 ml, 66.2 mmol) were placed in to the
reaction flask under nitrogen atmosphere. HBTU (3.27 g, 8.63 mmol),
EDCI (12.68 g, 66.2 mmol) and
(S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (15
g, 57.5 mmol) were added in this order and the mixture was stirred
overnight at RT. The solvent was distilled close to dryness under
vacuum, 2-propanol (25 ml) was added and the mixture was distilled
to dryness. 2-Propanol (127 ml) was added, heated to reflux, water
(23 ml) was added and the mixture was stirred for 15 min. The
mixture was cooled to RT, stirred overnight and cooled to 5.degree.
C. The precipitate was filtered, washed with 2.times.10 ml of cold
2-propanol:water (70:30) and dried under vacuum to obtain 18.7 g of
the title compound. .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta.
1.17 (d, 3H), 2.50 (s, 3H), 4.21-4.53 (m, 3H), 6.93 (d, 1H), 7.31
(s, 1H), 7.81 (d, 1H), 7.86-8.07 (m, 3H), 8.40-8.54 (bs, 1H), 14.14
(bs., 1H).
f)
N--((S)-1-(3-(3-Chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-5-(1-
-hydroxyethyl)-1H-pyrazole-3-carboxamide
Sodium borohydride (0.930 g, 24.57 mmol) and EtOH (105 ml) were
placed in to the reaction flask under nitrogen atmosphere.
(S)-3-acetyl-N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl)propan-2-y-
l)-1H-pyrazole-5-carboxamide (15 g, 37.8 mmol) was added in small
portions to keep temperature below 25.degree. C. After 3.5 h sodium
borohydride (0.07 g, 1.85 mmol) was added and the mixture was
stirred for additional 60 min to complete the reaction. 16 ml of
.about.10% HCl in EtOH was added carefully to set pH to 3.5 and the
mixture was stirred overnight at RT. Water (30 ml) was added and
the stirring was continued for 3 h. The precipitate was filtered,
washed with 2.times.10 ml of cold water:EtOH (1:1) and dried under
vacuum to obtain 12.2 g of the title compound. .sup.1H-NMR (400
MHz, DMSO-d.sub.6): .delta. 1.12 (, 3H), 1.39 (d, 3H), 4.24-4.52
(m, 3H), 4.76-4.86 (m, 1H), 5.42 (d, 1H), 6.42 (bs., 1H), 6.94 (d,
1H), 7.82 (d, 1H), 8.00 (bs, 2H), 8.09 (bs, 1H), 8.20 (d, 1H),
13.05 (bs, 1H).
g)
4-(1-(3-((S)-1-(3-(3-Chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-ylc-
arbamoyl)-1H-pyrazol-5-yl)ethoxy)-4-oxobutanoic acid
N--((S)-1-(3-(3-Chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-5-(1-h-
ydroxy-ethyl)-1H-pyrazole-3-carboxamide (1.254 mmol, 0.5 g),
dihydrofuran-2,5-dione (1.504 mmol, 0.151 g) and
4-dimethylaminopyridine (0.1254 mmol, 0.015 g) were dissolved in
THF (10 ml) and DMF (1 ml). The resulting mixture was stirred at RT
for one day after which the temperature was raised to 50.degree. C.
for one day. The mixture was stirred at RT over the weekend. During
the reaction more dihydrofuran-2,5-dione (50 mg) was added. The
solvents were evaporated and the residue was dissolved in EtOAc.
The organic phase was washed with 1 M HCl, separated, dried,
filtered and evaporated. The crude product was purified by flash
chromatography. 352 mg of the title compound was obtained.
.sup.1H-NMR (400 MHz, CDCl.sub.3): .delta. 1.22-1.28 (m, 3H),
1.61-1.69 (m, 3H), 2.54-2.79 (m, 4H), 4.29-4.45 (m, 2H), 4.52-4.64
(m, 1H), 5.97-6.06 (m, 1H), 6.58-6.62 (m, 1H), 6.76-6.80 (m, 1H),
7.50-7.53 (m, 1H), 7.62-7.68 (m, 1H), 7.70-7.77 (m, 1H), 7.90-8.04
(m, 2H).
Example 39
(S)-5-Chloro-N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)-propan-2-yl-
)pyrazine-2-carboxamide
a) 5-Chloropyrazine-2-carbonyl chloride
5-Chloropyrazine-2-carboxylic acid (3.15 mmol, 500 mg) was
dissolved in DCM (55 ml). Oxalyl dichloride (6.62 mmol, 841 mg) was
added slowly and the resulting mixture was refluxed for 2 h. After,
the reaction had stopped the mixture was concentrated. 580 mg of
the title compound was obtained. .sup.1H-NMR (400 MHz, CDCl.sub.3)
.delta. 8.78 (d, 1H), 9.09 (d, 1H).
b)
(S)-5-Chloro-N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2--
yl)pyrazine-2-carboxamide
5-Chloropyrazine-2-carbonyl chloride (3.28 mmol, 580 mg) was
dissolved in dry THF (40 ml). Triethylamine (9.83 mmol, 995 mg) and
(S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile
(3.28 mmol, 854 mg) were added and the resulting mixture was
stirred for one day at RT. The crude product was purified by
recrystallization from DCM. 900 mg of the title compound was
obtained. .sup.1H-NMR (400 MHz, CDCl.sub.3): .delta. 1.25 (d, 3H),
4.29 (dd, 1H), 4.47 (dd, 1H), 4.59-4.71 (m, 1H), 6.66 (d, 1H), 7.51
(d, 1H), 7.68-7.73 (m, 1H), 7.75-7.80 (m, 1H), 8.12 (d, 1H), 8.64
(d, 1H), 8.77 (d, 1H), 9.17 (d, 1H).
Example 40
N--((S)-1-(3-(3-Chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-1-((S)--
2-hydroxypropyl)-2-methyl-1H-imidazole-4-carboxamide
a)
(S)--N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-2-me-
thyl-1H-imidazole-4-carboxamide
2-Methyl-1H-imidazole-4-carboxylic acid (29.0 g, 230 mmol), 335 ml
of DMF and 165 ml of DCM were placed in to the reaction vessel
under nitrogen. HBTU (7.27 g, 19.18 mmol), EDCI (44.1 g, 230 mmol)
and 66.8 ml of DIPEA were added.
(S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (50
g, 192 mmol) was added and the reaction stirred overnight at RT.
600 ml of water was slowly added and water phase was washed with
335 ml and 500 ml of DCM. DCM phases were combined, washed with
3.times.600 ml of water and distilled to dryness. Acetonitrile (300
ml) was added and the mixture was heated up to 75.degree. C. Water
(300 ml) was added at >60.degree. C., solution was allowed to
cool to RT for precipitation and the mixture was stirred overnight
at RT. Stirring was continued for additional 2 h at <10.degree.
C. The precipitate was filtered, washed with cold ACN:water and
dried under vacuum to obtain 47 g of crude product. The title
compound was recrystallized from EtOH with 75% yield. .sup.1H-NMR
(400 MHz, DMSO-d.sub.6): .delta. 1.08 (d, 3H), 2.30 (s, 3H),
4.23-4.48 (m, 3H), 6.95 (d, 1H), 7.41 (s, 1H), 7.82 (d, 1H),
7.95-8.07 (m, 3H), 8.09-8.12 (m, 1H), 12.12 (bs, 1H).
b)
N--((S)-1-(3-(3-Chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-1-((-
S)-2-hydroxypropyl)-2-methyl-1H-imidazole-4-carboxamide
(S)--N-(1-(3-(3-Chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-2-meth-
yl-1H-imidazole-4-carboxamide (0.271 mmol, 100 mg) and potassium
carbonate (2.71 mmol, 375 mg) were dissolved in dry DMF (3 ml)
under nitrogen atmosphere. (S)-2-methyl-oxirane (0.298 mmol, 0.021
ml) was added and the resulting mixture was stirred for 2.5 h at
RT. The mixture was heated to 60.degree. C. for two days during
which more (S)-2-methyloxirane (0.252 ml) was added. The solvent
was evaporated and the residue was purified by flash
chromatography. 63 mg of the title compound was obtained.
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. 1.05 (d, 3H), 1.07 (d,
3H), 2.34 (s, 3H), 3.67-3.93 (m, 3H), 4.20-4.50 (m, 3H), 4.92 (bs,
1H), 6.95 (d, 1H), 7.47 (s, 1H), 7.83 (d, 1H), 7.98-8.00 (m, 2H),
8.04 (d, 1H), 8.11-8.12 (m, 1H).
Example 41
(S)-1-Butyl-N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)--
2-methyl-1H-imidazole-4-carboxamide
(S)--N-(1-(3-(3-Chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-2-meth-
yl-1H-imidazole-4-carboxamide (0.407 mmol, 150 mg),
triphenylphosphine (0.610 mmol, 160 mg) and 1-butanol (0.610 mmol,
45.2 mg) were dissolved in dry THF (5 ml) under nitrogen
atmosphere. DIAD (0.610 mmol, 123 mg) was slowly added. The
resulting mixture was stirred overnight at RT. At this point the
amounts of 1-butanol, triphenylphosphine and DIAD were doubled and
the stirring continued for another day. The solvent was evaporated
and the residue was purified by flash chromatography and
preparative HPLC, respectively. 22.8 mg of the title compound was
obtained. .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. 0.88 (t,
3H), 1.07 (d, 3H), 1.18-1.29 (m, 2H), 1.57-1.67 (m, 2H), 2.33 (s,
3H), 3.88 (t, 2H), 4.17-4.48 (m, 3H), 6.95 (d, 1H), 7.50 (s, 1H),
7.82 (d, 1H), 7.95-8.00 (m, 2H), 8.02 (d, 1H), 8.10 (s, 1H).
Example 42
(S)--N-(1-(3-(3-Chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-5-(2-hy-
droxypropan-2-yl)-1H-pyrazole-3-carboxamide
The title compound was prepared using the procedure described in
Example 3(h) starting from
5-(2-hydroxypropan-2-yl)-1H-pyrazole-3-carboxylic acid (0.646 mmol,
110 mg) and
(S)-4-(1-(2-amino-propyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile
(0.539 mmol, 140 mg) using DMF (2 ml) as the solvent. Water was
added and the mixture was extracted three times with DCM. The
combined organics were washed twice with water. The separated
organic phase was evaporated and the residue was purified by flash
chromatography and preparative HPLC, respectively. 44.6 mg of the
title compound was obtained. .sup.1H-NMR (400 MHz; DMSO-d.sub.6):
.delta. 1.11 (d, 3H), 1.45 (s, 6H), 4.22-4.52 (m, 3H), 5.31 (s,
1H), 6.37 (s, 1H), 6.94 (d, 1H), 7.81 (d, 1H), 7.88-8.03 (m, 2H),
8.09 (s, 1H), 8.16 (d, 1H), 12.96 (s, 1H).
Example 43
(S)--N-(1-(3-(3-Chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-1'-meth-
yl-1'H-1,4'-bipyrazole-3-carboxamide
The title compound was prepared using the procedure described in
Example 3(h) starting from
1'-methyl-1'H-[1,4'-bipyrazole]-3-carboxylic acid (0.921 mmol, 177
mg) and
(S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile
(0.767 mmol, 200 mg) using DMF (2 ml) as the solvent. DCM was added
and evaporated. The residue was purified by flash chromatography.
The product was further purified by dissolving it in DCM and
washing three times with 1 M NaHCO.sub.3 and evaporating the
separated DCM phase. 220 mg of the title compound was obtained.
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. 1.14 (d, 3H), 3.89 (s,
3H), 4.27-4.42 (m, 2H), 4.42-4.53 (m, 1H), 6.76 (d, 1H), 6.95 (d,
1H), 7.83-7.87 (m, 3H), 7.94 (dd, 1H), 8.06 (d, 1H), 8.16 (d, 1H),
8.18 (s, 1H), 8.21 (d, 1H).
Example 44
N--((S)-1-(3-(3-Chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-1-((R)--
2-hydroxypropyl)-2-methyl-1H-imidazole-4-carboxamide
The title compound was prepared using the procedure described in
Example 3(h) starting from
(R)-1-(2-hydroxypropyl)-2-methyl-1H-imidazole-4-carboxylic acid
(1.059 mmol, 195 mg) and
(S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-benzonitrile
(0.882 mmol, 230 mg) using DMF (2 ml) as the solvent. DCM was added
and evaporated. The residue was purified by flash chromatography.
The product was further purified by dissolving it in MeOH/DCM and
washing twice with 1 M NaHCO.sub.3. The separated organic phase was
dried, purified and evaporated. 289 mg of the title compound was
obtained. .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. 1.02-1.10
(m, 6H), 2.34 (s, 3H), 3.70-3.91 (m, 3H), 4.22-4.48 (m, 3H), 4.92
(d, 1H), 6.95 (d, 1H), 7.47 (s, 1H), 7.83 (d, 1H), 7.97-8.00 (m,
2H), 8.04 (d, 1H), 8.09-8.13 (m, 1H).
Example 45
(S)-2-Bromo-N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)-propan-2-yl)-
-1H-imidazole-4-carboxamide
The title compound was prepared using the procedure described in
Example 3(h) starting from 2-bromo-1H-imidazole-4-carboxylic acid
(5.75 mmol, 1.099 g) and
(S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile
(3.84 mmol, 1 g) using DMF (10 ml) as the solvent. DCM and water
were added, the phases were separated and the water phase was
extracted with DCM. The combined organics were washed three times
with water. The DCM phase was dried, filtered and evaporated. The
crude product was purified by flash chromatography and preparative
HPLC, respectively. 37.8 mg of the title compound was obtained.
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. 1.09 (d, 3H),
4.23-4.48 (m, 3H), 6.95 (d, 1H), 7.64 (s, 1H), 7.82 (d, 1H),
7.94-8.05 (m, 2H), 8.08 (s, 1H), 8.21 (d, 1H), 13.22 (bs, 1H).
Example 46
N--((S)-1-(3-(3-Chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-5-(1-hy-
droxy-2-methylpropyl)isoxazole-3-carboxamide
The title compound was prepared using the procedure described in
Example 3(h) starting from
5-(1-hydroxy-2-methyl-propyl)isoxazole-3-carboxylic acid (1.566
mmol, 290 mg) and
(S)-4-(1-(2-amino-propyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile
(1.044 mmol, 272 mg) using a mixture of DCM (5 ml) and DMF (1 ml)
as the solvent. DCM and water were added, the phases were separated
and the water phase was extracted with DCM. The combined organics
were washed twice with water. The DCM phase was dried, filtered and
evaporated. The crude product was purified by flash chromatography
and preparative HPLC, respectively. 23.4 mg of the title compound
was obtained. .sup.1H-NMR (400 MHz, CDCl.sub.3): .delta. 0.94 (d,
3H), 0.98 (d, 3H), 1.23 (d, 3H), 2.06-2.21 (m, 1H), 4.21-4.30 (m,
1H), 4.37-4.46 (m, 1H), 4.51-4.67 (m, 2H), 6.57-6.65 (m, 2H), 7.50
(d, 1H), 7.68 (d, 1H), 7.78-7.86 (m, 1H), 7.97 (d, 1H), 8.04 (s,
1H).
Example 47
(S)--N-(1-(3-(3-Chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-1-(2-cy-
anoethyl)-2-methyl-1H-imidazole-4-carboxamide
Sodium hydroxide, 5 M (1.085 mmol, 0.217 ml) and
(S)--N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl)propan-2-yl)-2-met-
hyl-1H-imidazole-4-carboxamide (0.542 mmol, 200 mg) were dissolved
in DMF (2 ml). The mixture was cooled to .about.10.degree. C. with
an ice bath and 3-bromopropionitrile (0.813 mmol, 109 mg) was
slowly added. The reaction mixture was allowed to warm to RT and it
was stirred overnight. The liquids were, evaporated. DCM was added
and washed twice with water. The separated organic phase was dried,
filtered and evaporated. The crude product was purified by flash
chromatography and preparative HPLC, respectively. 73.1 mg of the
title compound was obtained. .sup.1H-NMR (400 MHz, DMSO-d.sub.6):
.delta. 1.07 (d, 3H), 2.38 (s, 3H), 3.02 (t, 2H), 4.22 (t, 2H),
4.24-4.47 (m, 3H), 6.95 (d, 1H), 7.61 (s, 1H), 7.83 (d, 1H),
7.96-8.02 (m, 2H), 8.07-8.13 (m, 2H).
Example 48
N--((S)-1-(3-(3-Chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-1-(1-cy-
anoethyl)-2-methyl-1H-imidazole-4-carboxamide
Sodium hydroxide, 5 M (1.085 mmol, 0.217 ml) and
(S)--N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl)propan-2-yl)-2-met-
hyl-1H-imidazole-4-carboxamide (0.542 mmol, 200 mg) were dissolved
in DMF (2 ml). The mixture was cooled to .about.10.degree. C. with
an ice bath and 2-bromopropanenitrile (0.813 mmol, 109 mg) was
slowly added. The mixture was allowed to warm to RT and it was
stirred for 2 h. Solvent was evaporated, DCM was added and the
mixture was washed twice with water. The organic phase was dried,
filtered and evaporated. The crude product was purified by flash
chromatography and trituration from diethyl ether. 63 mg of the
title compound was obtained. .sup.1H-NMR (400 MHz, DMSO-d.sub.6):
.delta. 1.04-1.12 (m, 3H), 1.77 (d, 3H), 2.42 (s, 3H), 4.23-4.49
(m, 3H), 5.72 (q, 1H), 6.92-6.97 (m, 1H), 7.79-7.85 (m, 2H),
7.95-8.01 (m, 2H), 8.08-8.11 (m, 1H), 8.15 (d, 1H).
Example 49
(S)--N-(1-(3-(3-Chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-1-(2-me-
thylprop-1-enyl)-1H-pyrazole-3-carboxamide
The title compound was prepared using the procedure described in
Example 3(h) starting from
1-(2-methylprop-1-en-1-yl)-1H-pyrazole-3-carboxylic acid (1.151
mmol, 191 mg) and
(S)-4-(1-(2-amino-propyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile
(0.959 mmol, 250 mg) using DCM (5 ml) as the solvent. The mixture
was diluted with DCM and washed with 1 M Na.sub.2CO.sub.3. The
organic phase was dried, filtered and evaporated. The crude product
was purified flash chromatography. 297 mg of the title compound was
obtained. .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. 1.12 (d,
3H), 1.80 (d, 3H), 1.85 (d, 3H), 4.25-4.52 (m, 3H), 6.66 (d, 1H),
6.77-6.81 (m, 1H), 6.95 (d, 1H), 7.83 (t, 2H), 7.94-7.97 (m, 2H),
8.06-8.10 (m, 1H), 8.18 (d, 1H).
Example 50
(S)--N-(1-(3-(3-Chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-3-(1H-i-
midazol-4-yl)-1H-pyrazole-5-carboxamide
a)
(S)--N-(1-(3-(3-Chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-3-(1-
-trityl-1H-imidazol-4-yl)-1H-pyrazole-5-carboxamide
The title compound was prepared using the procedure described in
Example 3(h) starting from
3-(1-trityl-1H-imidazol-4-yl)-1H-pyrazole-5-carboxylic acid (2.493
mmol, 1048 mg) and
(S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-benzonitrile
(1.918 mmol, 500 mg) using a mixture of DCM (10 ml) and DMF (1 ml)
as the solvent. HBTU (0.384 mmol, 145 mg) was used instead of HOBt.
The reaction mixture was diluted with DCM and washed with 1 M
Na.sub.2CO.sub.3 and water. The separated organic phase was dried,
filtered and evaporated. 1.637 g of the title compound was
obtained. .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. 1.12 (d,
3H), 4.17-4.52 (m, 3H), 6.75 (bs., 1H), 6.92 (d, 1H), 7.12-7.19 (m,
7H), 7.35-7.53 (m, 12H), 7.80 (d, 1H), 7.97 (bs, 1H), 8.04 (s, 1H),
8.21 (d, 1H), 13.38 (bs., 1H).
b)
(S)--N-(1-(3-(3-Chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-3-(1-
H-imidazol-4-yl)-1H-pyrazole-5-carboxamide
Formic acid (452 mmol, 20.82 g) was dissolved in a mixture of water
(2 ml) and THF (40 ml).
(S)--N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-3-(1-t-
rityl-1H-imidazol-4-yl)-1H-pyrazole-5-carboxamide (1.508 mmol, 1 g)
was added and the resulting mixture was heated to 50.degree. C. for
3 h. The stirring continued for 2 days at RT. The mixture was
concentrated. ACN was added and evaporated. This was repeated once
more. The crude product was purified by flash chromatography. 0.371
g of the title compound was obtained. .sup.1H-NMR (400 MHz,
DMSO-d.sub.6): .delta. 1.14 (d, 3H), 4.23-4.56 (m, 3H), 6.76 (bs,
1H), 6.94 (d, 1H), 7.53 (bs, 1H), 7.76 (s, 1H), 7.83 (d, 1H),
7.95-8.04 (m, 2H), 8.07-8.10 (m, 1H), 8.27 (d, 1H), 12.30 (bs, 1H),
13.40 (bs, 1H).
Example 51
(S)--N-(1-(3-(3-Chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-1-cyclo-
propyl-1H-pyrazole-3-carboxamide
The title compound was prepared using the procedure described in
Example 32(e) starting from 1-cyclopropyl-1H-pyrazole-3-carboxylic
acid (0.300 g, 1.8 mmol) and
(S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-benzonitrile
(0.471 g, 1.8 mmol). The product was purified by
flash-chromatography. Yield: 400 mg. .sup.1H-NMR (400 MHz;
DMSO-d.sub.6): .delta. 0.98-1.11 (m, 7H), 3.75-3.80 (m, 1H),
4.25-4.48 (m, 3H), 6.54 (d, 1H), 6.96 (d, 1H), 7.82 (d, 2H),
7.93-7.99 (m, 2H), 8.07 (s, 1H), 8.16 (d, 1H), LC-MS:
[M+1]=395.15.
Example 52
(S)--N-(1-(3-(3-Chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-1-(6-(d-
imethylamino)pyridin-3-yl)-1H-pyrazole-3-carboxamide
a) Methyl 1H-imidazole-4-carboxylate
1H-Imidazole-4-carboxylic acid (5 g, 44.6 mmol) was dissolved in
MeOH (100 ml). Into the solution, H.sub.2SO.sub.4 (10 ml) was added
at 0.degree. C. The resulting mixture was stirred at 80.degree. C.
for overnight. The solvent was concentrated under reduced pressure.
The pH was adjusted to 9 with aqueous NaHCO.sub.3 solution and
extracted with EtOAc. The organic layer was concentrated to give
the product. Yield 5.2 g. .sup.1H-NMR (400 MHz; DMSO-d.sub.6):
.delta. 3.74 (s, 3H), 7.79 (bs, 2H), 12.75 (bs, 1H). LC-MS:
[M+1]=127.23.
b) Methyl
1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carboxylate
Into a flask containing methyl 1H-imidazole-4-carboxylate (5 g,
39.7 mmol) in DMF (70 ml), K.sub.2CO.sub.3 (13.7 g, 99.1 mmol),
SEM-Cl (9.3 ml, 51.6 mmol) were added and stirred at 80.degree. C.
overnight. The reaction mixture was quenched by the addition of
H.sub.2O and extracted with EtOAc. The organic layer was
concentrated and purified by column chromatography. Yield 3.8 g.
.sup.1H-NMR (400 MHz; DMSO-d.sub.6): .delta. 0.05 (s, 9H), 0.80 (t,
2H), 3.47 (t, 2H), 3.74 (s, 3H), 5.30 (s, 2H), 7.91 (s, 1H), 8.01
(s, 1H). LC-MS: [M+1]=257.27.
c) Methyl
2-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carb-
oxylate
Into a flask containing methyl
1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carboxylate
(4.0 g; 15.6 mmol) in CCl.sub.4 (100 ml), catalytic AIBN, NBS (3.1
g, 17.1 mmol) were added and stirred at 65.degree. C. for 3 h. The
reaction mixture was quenched with aqueous solution of NaHCO.sub.3
and extracted with EtOAc. The organic layer was concentrated and
purified by column chromatography. Yield 3.5 g. .sup.1H-NMR (400
MHz; DMSO-d.sub.6): .delta. 0.04 (s, 9H), 0.84 (t, 2H), 3.53 (t,
2H), 3.75 (s, 3H), 5.30 (s, 2H), 8.25 (s, 1H). LC-MS:
[M+1]=335.01.
d) Methyl
2-formyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-car-
boxylate
Into a flask containing methyl
2-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carboxylate
(5 g, 14.9 mmol) in THF (20 ml), 2 M solution of i-PrMgCl in THF
(22.4 ml, 44.9 mmol) was added at -40.degree. C. under nitrogen
atmosphere. The resulting mixture was allowed to stir for 10 min at
-40.degree. C. and cooled to -78.degree. C. The reaction mixture
was treated with DMF (7.29 ml, 89.8 mmol) and slowly warmed to RT.
The mixture was stirred for 1 h at RT and quenched with saturated
aqueous solution of NaHCO.sub.3. The crude was extracted with
EtOAc. The organic layer was concentrated under reduced pressure.
Yield 3 g. LC-MS: [M+1]=285.15.
e) Methyl
2-(hydroxymethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidaz-
ole-4-carboxylate
Into a flask containing a solution of methyl
2-formyl-1-((2-(trimethylsilyl)-ethoxy)-methyl)-1H-imidazole-4-carboxylat-
e (3 g, 10.5 mmol) in MeOH (20 ml), NaBH.sub.4 (0.401 g, 10.5 mmol)
was added in portions at 0.degree. C. The resulting mixture was
allowed to stir at 0.degree. C. for 30 min followed by RT for 1
hour. The reaction mixture was concentrated and the crude was
diluted with water and extracted with EtOAc. The organic layer was
concentrated under reduced pressure. Yield 1.5 g. LC-MS:
[M+1]=287.17.
f) Methyl
2-((tert-butyldimethylsilyloxy)methyl)-1-((2-(trimethylsilyl)eth-
oxy)methyl)-1H-imidazole-4-carboxylate
Into a flask containing a solution of methyl
2-(hydroxymethyl)-1-((2-(tri-methylsilyl)-ethoxy)methyl)-1H-imidazole-4-c-
arboxylate (1 g, 3.49 mmol) in DMF (25 ml), imidazole (0.490 g,
6.91 mmol), catalytic DMAP and TBDMSCl (0.790 g, 5.27 mmol) were
added. The resulting mixture was stirred at RT for 12 h. The
reaction mixture was quenched with saturated aqueous solution of
NaHCO.sub.3 and extracted with EtOAc. The organic layer was
concentrated and purified by flash column chromatography. Yield 800
mg. .sup.1H-NMR (400 MHz; DMSO-d.sub.6): .delta. -0.04 (s, 9H),
0.05 (s, 6H), 0.80 (t, 2H), 0.86 (s, 9H), 3.49 (t, 2H), 3.74 (s,
3H), 4.71 (s, 2H), 5.41 (s, 2H), 8.02 (s, 1H). LC-MS:
[M+1]=401.10.
g) (S)-2-((tert-Butyl
dimethylsilyloxy)methyl)-N-(1-(3-(3-chloro-4-cyano
phenyl)-1H-pyrazol-1-yl)propan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-
-1H-imidazole-4-carboxamide
Into a flask containing a solution of
(S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (0.4
g, 17.5 mmol) in toluene (20 ml), 2 M solution of trimethyl
aluminium in heptane (2.62 ml, 52.6 mmol) was added at 0.degree. C.
The resulting mixture was stirred at 0.degree. C. for 10 min and a
solution of methyl
2-((tert-butyldimethyl-silyloxy)methyl)-1-((2-(trimethylsilyl)ethoxy)meth-
yl)-1H-imidazole-4-carboxylate (0.7 g, 17.5 mmol) in toluene (20
ml) was added at 0.degree. C. The reaction mixture was heated at
110.degree. C. for 4 h and diluted with water. The mixture was
filtered through a celite bed and the filtrate was extracted with
EtOAc. The organic layer was concentrated under reduced pressure.
The product was purified by flash column chromatography. Yield 400
mg. .sup.1H-NMR (400 MHz; DMSO-d.sub.6): .delta. -0.05 (s, 9H),
0.05 (s, 6H), 0.82-0.84 (s, 11H), 1.14 (d, 3H), 3.47 (t, 2H),
4.26-4.40 (m, 3H), 4.74 (s, 2H), 5.38 (s, 2H), 6.94 (d, 1H), 7.73
(s, 1H), 7.83 (d, 1H), 7.99 (d, 2H), 8.10 (d, 2H). LC-MS:
[M+1]=629.38.
h)
(S)--N-(1-(3-(3-Chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-2-(h-
ydroxymethyl)-1H-imidazole-4-carboxamide hydrochloride
(S)-2-((tert-Butyldimethylsilyloxy)methyl)-N-(1-(3-(3-chloro-4-cyanopheny-
l)-1H-pyrazol-1-yl)propan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-im-
idazole-4-carboxamide (0.4 g, 15.9 mmol) in 6 N HCl (25 ml) was
stirred at 45.degree. C. for 24 h. The resulting mixture was
evaporated completely and triturated twice from diethyl ether. In
the end all precipitates were combined. Yield 200 mg. .sup.1H-NMR
(400 MHz; DMSO-d.sub.6): .delta. 1.19 (d, 3H), 4.31-4.34 (m, 3H),
4.68 (s, 2H), 6.93 (s, 1H), 7.89-7.95 (m, 3H), 8.05 (s, 1H), 8.30
(s, 1H), 9.15 (d, 1H), 14.8 (bs, 1H).
Example 53
(S)--N-(1-(3-(3-Chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-4,5,6,7-
-tetrahydropyrazolo[1,5-a]pyridine-2-carboxamide)
a)
(S)-2-Acetyl-N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2--
yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carboxamide
The title compound was prepared using the procedure described in
Example 32(e) starting from
2-acetyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carboxylic
acid (300 mg, 1.05 mmol) and
(S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzo-nitrile
(273 mg, 1.05 mmol). The product was purified with
flash-chromatography. Yield 366 mg. .sup.1H-NMR (400 MHz;
DMSO-d.sub.6): .delta. -0.09 (s, 9H), 0.81 (t, 2H), 1.15 (d, 3H),
2.6 (s, 3H), 3.49 (t, 2H), 4.31-4.47 (m, 3H), 5.66 (s, 2H), 6.95
(s, 1H), 7.85 (d, 1H), 7.92-7.97 (m, 2H), 8.06 (s, 2H), 8.17 (d,
1H).
b)
(S)-2-Acetyl-N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2--
yl)-1H-imidazole-4-carboxamide
The title compound was prepared using the procedure described in
Example 52(h) starting from
(S)-2-acetyl-N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl-
)-1-((2-(trimethylsilyl)ethoxy)-methyl)-1H-imidazole-4-carboxamide
(350 mg, 0.66 mmol). Yield 135 mg. .sup.1H-NMR (400 MHz;
DMSO-d.sub.6): .delta. 1.13 (d, 3H), 2.56 (s, 3H), 4.3-4.5 (m, 3H),
6.96 (s, 1H), 7.78 (d, 1H), 7.85 (d, 1H), 7.96 (s, 2H), 8.06 (s,
1H), 8.13 (d, 1H), 13.61 (s, 1H).
Example 54
N--((S)-1-(3-(3-Chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-2-(1-hy-
droxyethyl)-1H-imidazole-4-carboxamide
a)
N--((S)-1-(3-(3-Chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-2-(1-
-hydroxyethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carboxa-
mide
The title compound was prepared using the procedure described in
Example 33(e) starting from
(S)-2-acetyl-N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl-
)-1-((2-(trimethylsilyl)ethoxy)-methyl)-1H-imidazole-4-carboxamide
(300 mg, 0.57 mmol). The product was purified with flash
chromatography. Yield 270 mg. .sup.1H-NMR (400 MHz; DMSO-d.sub.6):
.delta. -0.05 (s, 9H), 0.84 (t, 2H), 1.08 (d, 3H), 1.49 (d, 3H),
3.45-3.5 (m, 2H), 4.27-4.31 (m, 1H), 4.37-4.46 (m, 2H), 4.87-4.93
(m, 1H), 5.4-5.5 (m, 3H), 6.96 (s, 1H), 7.68 (s, 1H), 7.84 (d, 1H),
7.95-8.03 (m, 3H), 8.11 (d, 1H).
b)
N--((S)-1-(3-(3-Chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-2-(1-
-hydroxyethyl)-1H-imidazole-4-carboxamide
The title compound was prepared using the procedure described in
Example 52(h) starting from
N--((S)-1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-2-(1-h-
ydroxyethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carboxami-
de (260 mg, 0.49 mmol). The product was purified by flash
chromategraphy. Yield 166 mg. .sup.1H-NMR (400 MHz; DMSO-d.sub.6):
.delta. 1.07 (d, 3H), 1.41 (d, 3H), 4.27-4.46 (m, 3H), 4.78 (s,
1H), 5.51 (d, 1H), 6.96 (d, 1H), 7.42 (d, 1H), 7.84 (d, 1H),
7.90-8.01 (m, 3H), 8.11 (s, 1H), 12.27 (s, 1H).
Example 55
(S)--N-(1-(3-(3-Chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-2-isopr-
opyl-1H-imidazole-4-carboxamide
a) Methyl 2-isopropyl-1H-imidazole-4-carboxylate
A solution of methyl 1H-imidazole-4-carboxylate (5.0 g, 39.68
mmol), AgNO.sub.3 (4.0 g, 23.81 mmol), isobutyric acid (10.4 g,
119.1 mmol) in 10% H.sub.2SO.sub.4 (150 ml) was heated at
80.degree. C. for 15 min. An aqueous solution of
(NH.sub.4).sub.2S.sub.2O.sub.8 (28.0 g, 119.1 mmol) was added to
the mixture dropwise in 15 min at 80.degree. C. The reaction
mixture was cooled to RT and poured into ice. The mixture was
basified with aqueous ammonia (pH 9) and extracted with EtOAc (500
ml). The organic layer was concentrated and the residue was
purified by flash chromatography. Yield 1.5 g. .sup.1H-NMR (400
MHz; CDCl.sub.3): .delta. 1.36 (d, 6H), 3.05-3.14 (m, 1H), 3.87 (s,
3H), 7.62 (s, 1H).
b) Methyl
2-isopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4--
carboxylate
Into a flask containing a solution of methyl
2-isopropyl-1H-imidazole-4-carboxylate (2.7 g, 16.1 mmol) in DMF
(20 ml), K.sub.2CO.sub.3 (5.5 g, 40.2 mmol) and SEM-Cl (3.5 g, 21.0
mmol) were added. The resulting mixture was heated at 80.degree. C.
for 18 h. The reaction mixture was diluted with H.sub.2O and
extracted with EtOAc. The product was purified with flash
chromatography. Yield 830 mg. .sup.1H-NMR (400 MHz; CDCl.sub.3):
.delta. 0.04 (s, 9H), 0.85-0.89 (m, 2H), 1.28 (d, 6H), 3.15-3.20
(m, 1H), 3.57 (t, 2H), 3.83 (s, 3H), 5.74 (s, 2H), 7.69 (s,
1H).
c)
2-Isopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carboxy-
lic acid
The title compound was prepared using the procedure described in
Example 32(d) starting from methyl
2-isopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carboxyla-
te (830 mg, 27.8 mmol). The product was triturated from ether and
pentane. Yield 430 mg. .sup.1H-NMR (400 MHz; DMSO-d.sub.6): .delta.
0.04 (s, 9H), 0.83 (t, 2H), 1.21 (s, 6H), 3.10-3.16 (m, 1H),
3.41-3.50 (m, 2H), 5.34 (s, 2H), 5.35 (s, 1H), 7.85 (s, 1H).
d)
(S)--N-(1-(3-(3-Chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-2-is-
opropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carboxamide
The title compound was prepared using the procedure described in
Example 32(e) starting from
2-isopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carboxyli-
c acid (0.430 g, 1.5 mmol) and
(S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile
(0.395 g, 1.5 mmol). Yield 360 mg. .sup.1H-NMR (400 MHz;
DMSO-d.sub.6): .delta. 0.06 (s, 9H), 0.80-0.85 (m, 2H), 1.10 (d,
3H), 1.21-1.24 (m, 6H), 3.08-3.15 (m, 1H), 3.43-3.47 (m, 2H),
4.30-4.44 (m, 3H), 5.32 (s, 2H), 6.96 (d, 1H), 7.63 (s, 1H),
7.85-7.87 (m, 2H), 7.93-7.95 (m, 2H), 8.09 (s, 1H).
e)
(S)--N-(1-(3-(3-Chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-2-is-
opropyl-1H-imidazole-4-carboxamide
The title compound was prepared using the procedure described in
Example 52(h) starting from
(S)--N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-2-isop-
ropyl-1-((2-(trimethylsilyl)-ethoxy)methyl)-1H-imidazole-4-carboxamide
(0.36 g, 0.6 mmol). Yield 127 mg. .sup.1H-NMR (400 MHz;
DMSO-d.sub.6): .delta. 1.08 (t, 3H), 1.23 (d, 6H), 2.94-3.01 (m,
1H), 4.27-4.44 (m, 3H), 6.96 (bs, 1H), 7.44 (s, 1H), 7.84 (s, 1H),
7.90-8.02 (m, 3H), 8.10 (s, 1H).
Example 56
(S)-2-Butyl-N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)--
1-methyl-1H-imidazole-4-carboxamide
a) Methyl 2-butyl-1H-imidazole-4-carboxylate
The title compound was prepared using the procedure described in
Example 55(a) starting from methyl 1H-imidazole-4-carboxylate (5 g,
39.7 mmol) and n-valeric acid (13 ml, 119 mmol). Yield: 1.2 g.
.sup.1H-NMR (400 MHz; CDCl.sub.3): .delta. 0.92 (t, 3H), 1.24-1.29
(m, 2H), 1.68-1.76 (m, 2H), 2.76 (t, 2H), 3.87 (s, 3H), 7.62 (s,
1H), 9.92 (bs, 1H).
b) Methyl 2-butyl-1-methyl-1H-imidazole-4-carboxylate
Into flask containing a solution of methyl
2-butyl-1H-imidazole-4-carboxylate (1.2 g, 6.6 mmol) in acetone (40
ml), Cs.sub.2CO.sub.3 (6.5 g, 19.8 mmol) and methyl iodide (0.5 ml,
6.6 mmol) were added. The reaction mixture was stirred at RT for 4
h and the solvent was evaporated. The residue was diluted with
water and extracted with EtOAc. The organic layer was concentrated
and purified with flash chromatography. Yield 500 mg. .sup.1H-NMR
(400 MHz; CDCl.sub.3): .delta. 0.937 (t, 3H), 1.35-1.44 (m, 2H),
1.68-1.75 (m, 2H), 2.69 (t, 2H), 3.62 (s, 3H), 3.86 (s, 3H), 7.50
(s, 1H).
c)
(S)-2-Butyl-N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-y-
l)-1-methyl-1H-imidazole-4-carboxamide
The title compound was prepared using the procedure described in
Example 52(g) starting from
(S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzo-nitrile
(664 mg, 2.55 mmol) and methyl
2-butyl-1-methyl-1H-imidazole-4-carboxylate (500 mg, 2.55 mmol).
The product was purified with flash chromatography. Yield 291 mg.
.sup.1H-NMR (400 MHz; DMSO-d.sub.6): .delta. 0.88 (t, 3H), 1.09 (t,
3H), 1.28-1.36 (m, 2H), 1.54-1.61 (m, 2H), 2.62 (t, 2H), 3.57 (s,
3H), 4.26-4.39 (m, 3H), 6.95 (bs, 1H), 7.47 (s, 1H), 7.82 (d, 1H),
7.90 (d, 1H), 7.96 (s, 2H), 8.09 (s, 1H).
Example 57
(S)--N-(1-(3-(3-Chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-2-(2-hy-
droxypropan-2-yl)-1-methyl-1H-imidazole-4-carboxamide
a) Methyl
2-(2-hydroxypropan-2-yl)-1-methyl-1H-imidazole-4-carboxylate
The title compound was prepared using the procedure described in
Example 2(d) starting from methyl
2-acetyl-1-methyl-1H-imidazole-4-carboxylate (400 mg, 2.19 mmol).
The product was purified with flash-chromatography. Yield 255 mg.
.sup.1H-NMR (400 MHz; DMSO-d.sub.6): .delta. 1.51 (s, 6H), 3.70 (s,
3H), 3.83 (s, 3H), 5.40 (s, 1H), 7.81 (s, 1H).
b)
(S)--N-(1-(3-(3-Chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-2-(2-
-hydroxypropan-2-yl)-1-methyl-1H-imidazole-4-carboxamide
The title compound was prepared using the procedure described in
Example 52(g) starting from methyl
2-(2-hydroxypropan-2-yl)-1-methyl-1H-imidazole-4-carboxylate (200
mg, 1 mmol) and
(S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-(trifluoromethyl)be-
nzonitrile (264 mg, 1 mmol). Yield 140 mg. .sup.1H-NMR (400 MHz;
DMSO-d.sub.6): .delta. 1.08 (d, 3H), 1.50 (s, 6H), 3.80 (s, 3H),
4.28-4.41 (m, 3H), 5.36 (s, 1H), 6.97 (d, 1H), 7.51 (s, 1H), 7.73
(d, 1H), 7.84 (d, 1H), 7.96 (s, 2H), 8.10 (d, 1H).
Example 58
(S)--N-(1-(3-(3-Chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-1-methy-
l-2-(1-methyl-1H-pyrazol-4-yl)-1H-imidazole-4-carboxamide
a)
Benzyl-2-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carb-
oxylate
Silver oxide (12.7 g, 54.8 mmol) was added to a solution of
2-bromo-1-((2-(trimethyl-silyl)ethoxy)methyl)-1H-imidazole-4-carboxylic
acid (11.7 g, 36.5 mmol) in ACN (200 ml) and stirred at RT for 10
min. Benzyl bromide (4.2 ml, 36.5 mmol) was added to the mixture
and stirred at RT for 12 h. The reaction mixture was filtered
through a celite bed and the filtrate was concentrated under
reduced pressure. The product was purified by flash chromatography.
Yield 10 g. .sup.1H-NMR (400 MHz; CDCl.sub.3): .delta. -0.04 (s,
9H), 0.92 (t, 2H), 3.54 (t, 2H), 5.29 (s, 2H), 5.35 (s, 2H),
7.30-7.44 (m, 5H), 7.76 (s, 1H).
b) Benzyl 2-bromo-1H-imidazole-4-carboxylate hydrochloride
The title compound was prepared using the procedure described in
Example 52(h) starting from
benzyl-2-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carbox-
ylate (16.2 g, 39.5 mmol). Yield 9.0 g. LC-MS: [M+1]=281.
c) Benzyl 2-bromo-1-methyl-1H-imidazole-4-carboxylate
The title compound was prepared using the procedure described in
Example 56(b) starting from benzyl
2-bromo-1H-imidazole-4-carboxylate hydrochloride (8.3 g, 29.4
mmol). The product was purified by flash chromatography. Yield 1.6
g. .sup.1H-NMR (400 MHz; CDCl.sub.3): .delta. 3.66 (s, 3H), 5.33
(s, 2H), 7.26-7.43 (m, 5H), 7.63 (s, 1H).
d) Benzyl
1-methyl-2-(1-methyl-1H-pyrazol-4-yl)-1H-imidazole-4-carboxylate
Into a flask containing a solution of benzyl
2-bromo-1-methyl-1H-imidazole-4-carboxylate (2 g, 6.77 mmol) in
1,2-dimethoxyethane (40 ml), potassium phosphate (2.3 g, 20.3 mmol)
and
1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole
(1.41 g, 6.77 mmol) were added at RT under argon atmosphere. The
resulting mixture was degassed and purged with argon for 10
minutes. Then Pd(PPh.sub.3).sub.4 (0.310 g, 0.2 mmol) was added to
the reaction mixture and heated at 90.degree. C. for 12 h. The
reaction mixture was filtered through a celite bed and the filtrate
was diluted with water and extracted with EtOAc. The organic layer
was concentrated and purified by flash chromatography. Yield 1.1 g.
.sup.1H-NMR (400 MHz; CDCl.sub.3): .delta. 3.77 (s, 3H), 3.95 (s,
3H), 5.36 (s, 2H), 7.30-7.37 (m, 3H), 7.45 (d, 2H), 7.59 (s, 1H),
7.79 (s, 1H), 7.89 (s, 1H).
e) 1-Methyl-2-(1-methyl-1H-pyrazol-4-yl)-1H-imidazole-4-carboxylic
acid
Into a flask containing a solution of benzyl
1-methyl-2-(1-methyl-1H-pyrazol-4-yl)-1H-imidazole-4-carboxylate (1
g, 3.4 mmol) in EtOH (25 ml), 10% Pd/C (100 mg) was added at RT.
The resulting mixture was stirred at RT under H.sub.2 atmosphere
for 3 h. The reaction mixture was filtered through a celite bed and
the filtrate was concentrated. The residue was triturated twice
from diethyl ether. Yield 500 mg. LC-MS: [M+1]=207.04.
f)
(S)--N-(1-(3-(3-Chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-1-me-
thyl-2-(1-methyl-1H-pyrazol-4-yl)-1H-imidazole-4-carboxamide
The title compound was prepared using the procedure described in
Example 32(e) starting from
1-methyl-2-(1-methyl-1H-pyrazol-4-yl)-1H-imidazole-4-carboxylic
acid (0.3 g, 1.44 mmol) and
(S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile
(0.377 g, 1.44 mmol). The product was purified by flash
chromatography. Yield 200 mg. .sup.1H-NMR (400 MHz; DMSO-d.sub.6):
.delta. 1.10 (d, 3H), 3.72 (s, 3H), 3.91 (s, 3H), 4.23-4.45 (m,
3H), 6.95 (d, 1H), 7.63 (d, 1H), 7.83 (t, 2H), 7.99 (d, 1H), 8.03
(d, 1H), 8.07 (s, 1H), 8.17 (s, 1H).
Example 59
(S)--N-(1-(3-(3-Chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-2-cyclo-
propyl-1-methyl-1H-imidazole-4-carboxamide
a) Benzyl 2-cyclopropyl-1-methyl-1H-imidazole-4-carboxylate
Into a solution of benzyl
2-bromo-1-methyl-1H-imidazole-4-carboxylate (2.8 g, 9.49 mmol) in
THF (40 ml) and water (20 ml), cesium carbonate (7.71 g, 23.7 mmol)
and cyclopropyl boronic acid (1.22 g, 14.2 mmol) were added under
argon atmosphere at RT. The resulting mixture was degassed and
purged with argon for 10 min. Pd(PPh.sub.3).sub.2Cl.sub.2 (0.332 g,
0.04 mmol) was added to the mixture and heated at 100.degree. C.
for 12 h. The reaction mixture was filtered through a celite bed
and the filtrate was diluted with water and extracted with EtOAc.
The organic layer was concentrated and purified by flash
chromatography. Yield 1.1 g. .sup.1H-NMR (400 MHz; CDCl.sub.3):
.delta. 0.95-1.02 (m, 2H), 1.07-1.11 (m, 2H), 1.72-1.78 (m, 1H),
3.70 (s, 3H), 5.32 (s, 2H), 7.29 (s, 1H), 7.42-7.62 (m, 5H), LC-MS:
[M+1]=257.
b) 2-Cyclopropyl-1-methyl-1H-imidazole-4-carboxylic acid
The title compound was prepared using the procedure described in
Example 58(e) starting from benzyl
2-cyclopropyl-1-methyl-1H-imidazole-4-carboxylate (1.1 g, 1.95
mmol). Yield 400 mg. LC-MS: [M+1]=167.06.
c)
(S)--N-(1-(3-(3-Chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-2-cy-
clopropyl-1-methyl-1H-imidazole-4-carboxamide
The title compound was prepared using the procedure described in
Example 32(e) starting from
2-cyclopropyl-1-methyl-1H-imidazole-4-carboxylic acid (0.160 g,
0.96 mmol) and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro
benzonitrile (0.251 g, 0.96 mmol). The product was purified with
flash chromatography. Yield 166 mg. .sup.1H-NMR (400 MHz;
DMSO-d.sub.6): .delta. 0.80-0.92 (m, 4H), 1.07 (d, 3H), 1.94-1.98
(m, 1H), 3.65 (s, 3H), 4.26-4.38 (m, 3H), 6.95 (s, 1H), 7.47 (s,
1H), 7.75 (d, 1H), 7.81 (s, 1H); 7.96 (s, 2H), 8.08 (s, 1H). LC-MS:
[M+1]=409.28.
Example 60
(S)--N.sup.4-(1-(3-(3-Chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-1-
H-imidazole-2,4-dicarboxamide
a)
(S)--N.sup.4-(1-(3-(3-Chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl-
)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-2,4-dicarboxamide
The title compound was prepared using the procedure described in
Example 32(e) starting from
2-carbamoyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carboxyli-
c acid (400 mg, 1.4 mmol) and
(S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (366
mg, 1.4 mmol). The product was purified with flash-chromatography.
Yield 410 mg. LC-MS: [M+1]=528.24.
b)
(S)--N.sup.4-(1-(3-(3-Chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl-
)-1H-imidazole-2,4-dicarboxamide
The title compound was prepared using the procedure described in
Example 52(g) starting from
(S)--N.sup.4-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl)propan-2-yl)-
-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-2,4-dicarboxamide
(0.41 g, 0.77 mmol). Yield 310 mg. .sup.1H-NMR (400 MHz;
DMSO-d.sub.6): .delta. 1.13 (d, 3H), 4.32-4.50 (m, 3H), 6.96 (s,
1H), 7.64 (s, 2H), 7.72 (s, 1H), 7.85 (s, 1H), 7.93-7.98 (m, 3H),
8.06 (s, 1H), 13.40 (s, 1H).
Example 61
(S)--N-(1-(3-(4-Cyano-3-(trifluoromethyl)phenyl)-1H-pyrazol-1-yl)propan-2--
yl)-2-(2-hydroxypropan-2-yl)oxazole-4-carboxamide
The title compound was prepared using the procedure described in
Example 32(e) starting from
2-(2-hydroxypropan-2-yl)-oxazole-4-carboxylic acid (0.3 g, 1.75
mmol) and
(S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-(trifluoromethyl)benzonitrile
(0.516 mg, 1.75 mmol). The product was purified by column
chromatography. Yield 270 mg. .sup.1H-NMR (400 MHz; DMSO-d6):
.delta. 1.13 (d, 3H), 1.51 (s, 6H), 4.30-4.52 (m, 3H), 5.67 (s,
1H), 7.05 (s, 1H), 7.86 (d, 1H), 8.17 (d, 2H), 8.28 (d, 2H), 8.47
(s, 1H).
Example 62
(S)--N-(2-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propyl)-2-(-
2-hydroxypropan-2-yl)oxazole-4-carboxamide
a)
(S)-4-(1-(1-Aminopropan-2-yl)-1H-pyrazol-3-yl)-2-chloro-6-fluoro-benzon-
itrile
The title compound was prepared using the procedure described in
Example 3(g) starting from
2-chloro-6-fluoro-4-(1H-pyrazol-3-yl)benzonitrile (13.5 mmol, 3 g)
and (R)-tert-butyl (2-hydroxypropyl)carbamate (27 mmol, 4.72 g).
Yield 1.3 g. .sup.1H-NMR (400 MHz; CDCl.sub.3): .delta. 1.47 (d,
3H), 3.02-3.19 (m, 2H), 4.30-4.38 (m, 1H), 6.60 (d, 1H), 7.52-7.59
(m, 2H), 7.75 (s, 1H). LC-MS: [M+1]=279.17.
b)
(S)--N-(2-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propyl)--
2-(2-hydroxypropan-2-yl)oxazole-4-carboxamide
The title compound was prepared using the procedure described in
Example 52(g) starting from ethyl
2-(2-hydroxypropan-2-yl)oxazole-4-carboxylate (0.75 mmol, 150 mg)
and
(S)-4-(1-(1-aminopropan-2-yl)-1H-pyrazol-3-yl)-2-chloro-6-fluorobenzonitr-
ile (0.75 mmol, 209 mg). Yield 87 mg. .sup.1H-NMR (400 MHz;
DMSO-d.sub.6): .delta. 1.45 (d, 3H), 1.49 (s, 6H), 3.55-3.61 (m,
1H), 3.66-3.73 (m, 1H), 4.69-4.74 (m, 1H), 5.66 (s, 1H), 7.03 (d,
1H), 7.88-7.93 (m, 2H), 8.0 (s, 1H), 8.19 (t, 1H), 8.51 (s, 1H).
LC-MS: [M+1]=432.31.
Example 63
(R)--N-(2-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propyl)-2-(-
2-hydroxypropan-2-yl)oxazole-4-carboxamide
a)
(R)-4-(1-(1-Aminopropan-2-yl)-1H-pyrazol-3-yl)-2-chloro-6-fluoro-benzon-
itrile
The title compound was prepared using the procedure described in
Example 3(g) starting from
2-chloro-6-fluoro-4-(1H-pyrazol-3-yl)benzonitrile (14.9 mmol, 3.3
g) and (S)-tert-butyl (2-hydroxypropyl)carbamate (29.8 mmol, 5.23
g). Yield 2.2 g. .sup.1H-NMR (400 MHz; CDCl.sub.3): .delta. 1.53
(d, 3H), 3.44-3.61 (m, 2H), 4.48-4.54 (m, 1H), 6.59 (d, 1H), 7.48
(d, 1H), 7.55 (d, 1H), 7.75 (s, 1H). LC-MS: [M+1]=279.12.
b)
(R)--N-(2-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propyl)--
2-(2-hydroxypropan-2-yl)oxazole-4-carboxamide
The title compound was prepared using the procedure described in
Example 52(g) starting from ethyl
2-(2-hydroxypropan-2-yl)oxazole-4-carboxylate (0.5 mmol, 139 mg)
and
(R)-4-(1-(1-aminopropan-2-yl)-1H-pyrazol-3-yl)-2-chloro-6-fluoro-benzonit-
rile (0.5 mmol, 100 mg). Yield 27 mg. .sup.1H-NMR (400 MHz;
DMSO-d.sub.6): .delta. 1.45 (d, 3H), 1.49 (s, 6H), 3.55-3.61 (m,
1H), 3.66-3.73 (m, 1H), 4.67-4.76 (m, 1H), 5.65 (s, 1H), 7.03 (d,
1H), 7.88 (d, 1H), 7.91 (d, 1H), 8.0 (s, 1H), 8.19 (t, 1H), 8.51
(s, 1H). LC-MS: [M+1]=432.02.
Example 64
(R)--N-(2-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propyl)-2-(-
2-hydroxypropan-2-yl)-1H-imidazole-4-carboxamide
a)
(R)--N-(2-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propyl)--
2-(2-hydroxypropan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-
-4-carboxamide
The title compound was prepared using the procedure described in
Example 32(e) starting from
2-(2-hydroxypropan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-
e-4-carboxylic acid (1.43 mmol, 430 mg) and
(R)-4-(1-(1-aminopropan-2-yl)-1H-pyrazol-3-yl)-2-chloro-6-fluorobenzonitr-
ile (1.43 mmol, 400 mg). The product was purified by
flash-chromatography. Yield 410 mg. LC-MS: [M+1]=561.21.
b)
(R)--N-(2-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propyl)--
2-(2-hydroxypropan-2-yl)-1H-imidazole-4-carboxamide
The title compound was prepared using the procedure described in
Example 52(h) starting from
(R)--N-(2-(3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propyl)-2--
(2-hydroxypropan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-
-carboxamide (0.73 mmol, 410 mg). Yield 130 mg. .sup.1H-NMR (400
MHz; DMSO-d.sub.6): .delta. 1.42 (s, 6H), 1.44 (d, 3H), 3.56-3.69
(m, 2H), 4.67-4.71 (m, 1H), 5.31 (s, 1H), 7.04 (bs, 1H), 7.40 (bs,
1H), 7.76 (bs, 1H), 7.90 (d, 1H), 7.94 (s, 1H), 8.01 (s, 1H), 12.17
(s, 1H). LC-MS: [M+1]=431.22.
Example 65
(S)--N-(1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-yl-
)-2-(2,2,2-trifluoroethyl)-1H-imidazole-4-carboxamide
a) 3,3,3-Trifluoro-N'-hydroxypropanimidamide
Into a flask containing sodium (45.87 mmol, 2.5 g) in MeOH (10 ml),
a suspension of NH.sub.2OH.HCl (45.87 mmol, 3.2 g) in MeOH (11 ml)
was added using a dropping funnel. After addition, the mixture was
stirred for 15 min. The suspension was filtered to remove the
precipitated NaCl. The filtrate was cooled to 0.degree. C. and
3,3,3-trifluoropropionitrile (45.87 mmol, 5 g) was added. The
reaction mixture was stirred for 1 h. The solvent was evaporated
under reduced pressure. The crude product was proceeded to the next
step without purification. Yield 3.0 g.
b) Ethyl
3-(((1-amino-3,3,3-trifluoropropylidene)amino)oxy)acrylate
Into a flask containing 3,3,3-trifluoro-N'-hydroxypropanimidamide
(21 mmol, 3 g) in ACN (50 ml), Et.sub.3N (21 mmol, 3.5 ml) was
added at RT. The resulting mixture was heated at 80.degree. C. and
a solution of ethyl propiolate (25.1 mmol, 2.5 g) in ACN (20 ml)
was added. The reaction mixture was heated at 80.degree. C. for
overnight. The solvent was evaporated and the crude was purified by
flash-chromatography. Yield 3.8 g. .sup.1H-NMR (400 MHz;
DMSO-d.sub.6): .delta. 1.17 (t, 3H), 3.18 (q, 2H), 4.09 (q, 2H),
5.44 (d, 1H), 6.78 (bs, 2H), 7.70 (d, 1H). LC-MS: [M-1]=239.17.
c) Ethyl 2-(2,2,2-trifluoroethyl)-1H-imidazole-4-carboxylate
Ethyl 3-(((1-amino-3,3,3-trifluoropropylidene)amino)oxy)acrylate
(4.17 mmol, 1 g) was dissolved in diphenyl ether (2 ml) and heated
at 180.degree. C. for 30 min. The reaction mixture was adsorbed on
silica gel and purified by column-chromatography. Yield 120 mg.
.sup.1H-NMR (400 MHz; DMSO-d.sub.6+D.sub.2O): .delta. 1.23 (t, 3H),
3.73 (q, 2H), 4.19 (q, 2H), 7.80 (s, 1H). LC-MS: [M+1]=223.14.
d) Ethyl
2-(2,2,2-trifluoroethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H--
imidazole-4-carboxylate
The title compound was prepared using the procedure described in
Example 52(b) starting from ethyl
2-(2,2,2-trifluoroethyl)-1H-imidazole-4-carboxylate (3.6 mmol, 0.8
g) and SEM-Cl (4.3 mmol, 0.8 ml). Yield 602 mg. .sup.1H-NMR (400
MHz; CDCl.sub.3): .delta. 0.01 (s, 9H), 0.91 (t, 2H), 1.39 (t, 3H),
3.48 (t, 2H), 3.75 (q, 2H), 4.39 (q, 2H), 5.33 (s, 2H), 7.69 (s,
1H).
e)
2-(2,2,2-Trifluoroethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidaz-
ole-4-carboxylic acid
Ethyl
2-(2,2,2-trifluoroethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-im-
idazole-4-carboxylate (2.41 mmol, 850 mg) was dissolved in THF (30
ml) and H.sub.2O (20 ml). NaOH (4.82 mmol, 200 mg) was added and
the mixture was stirred at RT for 48 h. The reaction mixture was
concentrated and acidified to pH 2 using 1 N HCl. The mixture was
extracted with DCM and the organic layer was concentrated. Yield
310 mg. LC-MS: [M+1]=325.01.
f)
(S)--N-(1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-
-yl)-2-(2,2,2-trifluoroethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imid-
azole-4-carboxamide
The title compound was prepared using the procedure described in
Example 32(e) starting from
2-(2,2,2-trifluoroethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-
e-4-carboxylic acid (0.98 mmol, 320 mg) and
(S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-6-fluorobenzonitrile
(0.98 mmol, 273 mg). The product was purified by
flash-chromatography. Yield 310 mg. LC-MS: [M+1]=585.25.
g)
(S)--N-(1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-
-yl)-2-(2,2,2-trifluoroethyl)-1H-imidazole-4-carboxamide
The title compound was prepared using the procedure described in
Example 52(h) starting from
(S)--N-(1-(3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-y-
l)-2-(2,2,2-trifluoroethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidaz-
ole-4-carboxamide (0.74 mmol, 430 mg). Yield 220 mg. .sup.1H-NMR
(400 MHz; DMSO-d.sub.6): .delta. 1.07 (d, 3H), 3.73 (q, 2H),
4.24-4.47 (m, 3H), 7.03 (s, 1H), 7.61 (s, 1H), 7.80-7.98 (m, 2H),
8.0 (s, 1H), 8.10 (d, 1H), 12.64 (s, 1H). LC-MS: [M+1]=455.12.
Example 66
(S)--N-(1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-yl-
)-2-(trifluoromethyl)-1H-imidazole-4-carboxamide
a) 2,2,2-Trifluoro-N'-hydroxyacetimidamide
The title compound was prepared using the procedure described in
Example 65(a) starting from 2,2,2-trifluoroacetonitrile (558 mmol,
53 g) and NH.sub.2OH.HCl (558 mmol, 39 g). The crude product was
used directly for the next step. Yield 70 g.
b) Ethyl
3-(((1-amino-2,2,2-trifluoroethylidene)amino)oxy)acrylate
The title compound was prepared using the procedure described in
Example 65(b) starting from 2,2,2-trifluoro-N'-hydroxyacetimidamide
(218.7 mmol, 28 g) and ethyl propiolate (262.5 mmol, 25.7 g). Yield
45.2 g. .sup.1H-NMR (400 MHz; DMSO-d.sub.6): .delta. 1.32 (t, 3H),
4.31 (q, 2H), 7.03 (d, 1H), 7.60 (bs, 2H), 8.29 (d, 1H). LC-MS:
[M-1]=225.34.
c) Ethyl 2-(trifluoromethyl)-1H-imidazole-4-carboxylate
The title compound was prepared using the procedure described in
Example 65(c) starting from ethyl
3-(((1-amino-2,2,2-trifluoroethylidene)amino)oxy)acrylate (4.42
mmol, 1 g). Yield 177 mg. .sup.1H-NMR (400 MHz; DMSO-d.sub.6):
.delta. 1.28 (t, 3H), 4.27 (q, 2H), 8.16 (s, 1H), 14.27 (bs, 1H).
LC-MS: [M+1]=209.32.
d) Ethyl
2-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imida-
zole-4-carboxylate
The title compound was prepared using the procedure described in
Example 52(b) starting from ethyl
2-(trifluoromethyl)-1H-imidazole-4-carboxylate (9.5 mmol, 2 g) and
SEM-Cl (11.5 mmol, 2.1 ml). Yield 1.9 g. .sup.1H-NMR (400 MHz;
CDCl.sub.3): .delta. -0.01 (s, 9H), 0.91 (t, 2H), 1.40 (t, 3H),
3.54 (t, 2H), 4.40 (q, 2H), 5.43 (s, 2H), 7.85 (s, 1H).
e)
2-(Trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-
-carboxylic acid
The title compound was prepared using the procedure described in
Example 32(d) starting from ethyl
2-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-c-
arboxylate (2.06 mmol, 700 mg). Yield 601 mg. .sup.1H-NMR (400 MHz;
DMSO-d.sub.6): .delta. -0.07 (s, 9H), 0.82 (t, 2H), 3.54 (t, 2H),
5.85 (s, 2H), 7.78 (s, 1H). LC-MS: [M+1]=311.07.
f)
(S)--N-(1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-
-yl)-2-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-
-4-carboxamide
The title compound was prepared using the procedure described in
Example 32(e) starting from
2-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-c-
arboxylic acid (0.97 mmol, 300 mg) and
(S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-6-fluorobenzonitrile
(0.97 mmol, 269 mg). The product was purified by
flash-chromatography. Yield 230 mg. .sup.1H-NMR (400 MHz;
DMSO-d.sub.6): .delta. -0.13 (s, 9H), 0.65-0.77 (m, 2H), 1.17 (d,
3H), 3.36-3.43 (m, 2H), 4.21-4.42 (m, 3H), 5.75 (q, 2H), 7.01 (s,
1H), 7.64 (s, 1H), 7.83-7.88 (m, 2H), 7.95 (s, 1H), 8.65 (d, 1H).
LC-MS: [M+1]=571.01.
g)
(S)--N-(1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-
-yl)-2-(trifluoromethyl)-1H-imidazole-4-carboxamide
The title compound was prepared using the procedure described in
Example 52(h) starting from
(S)--N-(1-(3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-y-
l)-2-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-
-carboxamide (0.39 mmol, 220 mg). Yield 153 mg. .sup.1H-NMR (400
MHz; DMSO-d.sub.6): .delta. 1.12 (d, 3H), 4.28-4.49 (m, 3H), 7.01
(d, 1H), 7.82-7.87 (m, 3H), 7.95 (s, 1H), 8.23 (d, 1H), 14.08 (s,
1H). LC-MS: [M+1]=441.17.
Example 67
N--((S)-1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-yl-
)-3-((S)-1-hydroxyethyl)-1,2,4-oxadiazole-5-carboxamide and
N--((S)-1-(3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-yl-
)-3-((R)-1-hydroxyethyl)-1,2,4-oxadiazole-5-carboxamide
a) 2-((tert-Butyldiphenylsilyl)oxy)propanenitrile
Into a flask containing DL-lactonitrile (36.3 mmol, 2.8 g) in DCM
(25 ml), Et.sub.3N (54.7 mmol, 8.1 ml) and tert-butyldiphenylsilyl
chloride (36.3 mmol, 10 g) were added. The resulting solution was
stirred at RT for 24 h. The reaction mixture was quenched with
H.sub.2O and extracted with DCM. The organic layer was washed with
brine, dried, filtered and evaporated. The crude product was
purified by flash-chromatography. Yield 4.52 g. .sup.1H-NMR (400
MHz; CDCl.sub.3): .delta. 1.10 (s, 9H), 1.50 (d, 3H), 4.43 (q, 1H),
7.39-7.51 (m, 6H), 7.65 (d, 2H), 7.71 (d, 2H).
b) 2-((tert-Butyldiphenylsilyl)oxy)-N'-hydroxypropanimidamide
Into a flask containing
2-((tert-butyldiphenylsilyl)oxy)propanenitrile (14.6 mmol, 4.5 g)
in MeOH (50 ml), NH.sub.2OH.HCl (29.1 mmol, 2 g) and NaHCO.sub.3
(43.7 mmol, 3.6 g) were added. The resulting mixture was stirred at
70.degree. C. for overnight. The mixture was quenched with H.sub.2O
and extracted with EtOAc. The organic layer was washed with
H.sub.2O, dried, filtered and evaporated. Yield 4.02 g. .sup.1H-NMR
(400 MHz; DMSO-d.sub.6): .delta. 1.01 (s, 9H), 1.20 (d, 3H), 4.12
(q, 1H), 7.38-7.46 (m, 6H), 7.60-7.64 (m, 4H). LC-MS:
[M+1]=343.12.
c) Ethyl
3-(1-((tert-butyldiphenylsilyl)oxy)ethyl)-1,2,4-oxadiazole-5-carb-
oxylate
The title compound was prepared using the procedure described in
Example 5(a) starting from
2-((tert-butyldiphenylsilyl)oxy)-N'-hydroxypropanimidamide (3.24
mmol, 1 g). Yield 618 mg. .sup.1H-NMR (400 MHz; CDCl.sub.3):
.delta. 1.07 (s, 9H), 1.46 (t, 3H), 1.52 (d, 3H), 4.53 (q, 2H),
5.09 (q, 1H), 7.30-7.47 (m, 6H), 7.61 (d, 2H), 7.69 (d, 2H).
d) Ethyl 3-(1-hydroxyethyl)-1,2,4-oxadiazole-5-carboxylate
Ethyl
3-(1-((tert-butyldiphenylsilyl)oxy)ethyl)-1,2,4-oxadiazole-5-carbox-
ylate (5.90 mmol, 2.5 g) was dissolved in THF and cooled to
0.degree. C. with an ice bath. 70% Hydrogen fluoride in pyridine
(1.5 ml) was added slowly. After addition, the reaction mixture was
stirred at ambient temperature for overnight. The reaction mixture
was basified by aqueous NaHCO.sub.3 solution and extracted with
DCM. The organic layers were washed with water, dried, filtered and
evaporated. The product was purified by flash-chromatography. Yield
897 mg. .sup.1H-NMR (400 MHz; CDCl.sub.3): .delta. 1.46 (t, 3H),
1.66 (d, 3H), 4.53 (q, 2H), 5.11 (q, 1H).
e)
N--((S)-1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-
-yl)-3-((S)-1-hydroxyethyl)-1,2,4-oxadiazole-5-carboxamide
(Diastereomer 1) and
N--((S)-1-(3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-yl-
)-3-((R)-1-hydroxyethyl)-1,2,4-oxadiazole-5-carboxamide
(Diastereomer 2)
The title compounds were prepared using the procedure described in
Example 52(g) starting from ethyl
3-(1-hydroxyethyl)-1,2,4-oxadiazole-5-carboxylate (9.67 mmol, 1.8
g) and
(S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-6-fluorobenzonitrile
(9.67 mmol, 2.62 g). Yield 1.02 g (mixture of diastereomers). The
reaction produced the diastereomeric mixture of
N--((S)-1-(3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-y-
l)-3-((S)-1-hydroxyethyl)-1,2,4-oxadiazole-5-carboxamide and
N--((S)-1-(3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-y-
l)-3-((R)-1-hydroxyethyl)-1,2,4-oxadiazole-5-carboxamide. Both
diastereomers were separated by column-chromatography.
Diastereomer 1: .sup.1H-NMR (400 MHz; DMSO-d.sub.6): .delta. 1.19
(d, 3H), 1.44 (d, 3H), 4.34 (d, 2H), 4.43-4.51 (m, 1H), 4.91 (q,
1H), 5.84 (d, 1H), 7.02 (d, 1H), 7.84-7.87 (m, 2H), 7.96 (s, 1H),
9.46 (d, 1H). LC-MS: [M+1]=419.12.
Diastereomer 2: .sup.1H-NMR (400 MHz; DMSO-d.sub.6): .delta. 1.18
(d, 3H), 1.44 (d, 3H), 4.34 (d, 2H), 4.43-4.50 (m, 1H), 4.91 (q,
1H), 5.84 (d, 1H), 7.02 (d, 1H), 7.80-7.90 (m, 2H), 7.96 (s, 1H),
9.46 (d, 1H). LC-MS: [M+1]=419.07.
Example 68
(S)--N-(2-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propyl)-3-(-
2-hydroxypropan-2-yl)-1,2,4-oxadiazole-5-carboxamide
a) Ethyl 3-acetyl-1,2,4-oxadiazole-5-carboxylate
Into a flask containing ethyl
3-(1-hydroxyethyl)-1,2,4-oxadiazole-5-carboxylate (53.7 mmol, 10 g)
in DCM (100 ml), Dess-Martin periodinane (80 mmol, 34.2 g) was
added at 0.degree. C. in portions and the resulting mixture was
stirred at RT for 16 h. The reaction mixture was quenched with
aqueous NaHCO.sub.3 solution and extracted with DCM. The organic
layers were dried, filtered and evaporated. The product was
purified by flash-chromatography. Yield 9.12 g. .sup.1H-NMR (400
MHz; CDCl.sub.3): .delta. 1.47 (t, 3H), 2.76 (s, 3H), 4.58 (q,
2H).
b) Ethyl
3-(2-hydroxypropan-2-yl)-1,2,4-oxadiazole-5-carboxylate
The title compound was prepared using the procedure described in
Example 2(d) starting from ethyl
3-acetyl-1,2,4-oxadiazole-5-carboxylate (10.8 mmol, 2 g). Yield 304
mg. .sup.1H-NMR (400 MHz; CDCl.sub.3): .delta. 1.39 (t, 3H), 1.59
(s, 6H), 4.54 (q, 2H). LC-MS: [M+1]=201.04.
c)
(S)--N-(2-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propyl)--
3-(2-hydroxypropan-2-yl)-1,2,4-oxadiazole-5-carboxamide
The title compound was prepared using the procedure described in
Example 52(g) starting from ethyl
3-(2-hydroxypropan-2-yl)-1,2,4-oxadiazole-5-carboxylate (1.5 mmol,
300 mg) and
(S)-4-(1-(1-aminopropan-2-yl)-1H-pyrazol-3-yl)-2-chloro-6-fluorob-
enzonitrile (1.5 mmol, 417 mg). Yield 160 mg. .sup.1H-NMR (400 MHz;
DMSO-d.sub.6): .delta. 1.49 (bs, 9H), 3.57-3.64 (m, 1H), 3.68-3.76
(m, 1H), 4.69-4.75 (m, 1H), 5.69 (s, 1H), 7.02 (d, 1H), 7.89 (d,
1H), 7.94 (d, 1H), 7.99 (s, 1H), 9.46 (t, 1H). LC-MS:
[M+1]=433.17.
Example 69
(S)--N-(1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-yl-
)-3-(2-hydroxypropan-2-yl)-1,2,4-oxadiazole-5-carboxamide
The title compound was prepared using the procedure described in
Example 52(g) starting from ethyl
3-(2-hydroxypropan-2-yl)-1,2,4-oxadiazole-5-carboxylate (2 mmol,
400 mg) and
(S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-6-fluoro-benzonitr-
ile (2 mmol, 556 mg). Yield 202 mg. .sup.1H-NMR (400 MHz;
DMSO-d.sub.6): .delta. 1.12 (d, 3H), 1.51 (bs, 6H), 4.34-4.37 (m,
2H), 4.43-4.51 (m, 1H), 5.70 (s, 1H), 7.02 (d, 1H), 7.83-7.88 (m,
2H), 7.96 (s, 1H), 9.41 (d, 1H). LC-MS: [M+1]=433.20.
Example 70
(S)--N-(1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-yl-
)-2-cyclopropyl-1H-imidazole-4-carboxamide
a) Benzyl
2-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole--
4-carboxylate
The title compound was prepared using the procedure described in
Example 59(a) starting from benzyl
2-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carboxylate
(7.31 mmol, 3 g) and cyclopropylboronic acid (14.63 mmol, 1.25 g).
Yield 1.02 g. .sup.1H-NMR (400 MHz; CDCl.sub.3): .delta. -0.02 (s,
9H), 0.91 (t, 2H), 0.99 (bs, 2H), 1.15 (bs, 2H), 1.87-1.94 (m, 1H),
3.52 (t, 2H), 5.32 (s, 2H), 5.34 (s, 2H), 7.29-7.43 (m, 5H), 7.59
(s, 1H). LC-MS: [M+1]=373.31.
b)
2-Cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carbo-
xylic acid
The title compound was prepared using the procedure described in
Example 58(e) starting from benzyl
2-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carboxy-
late (2.68 mmol, 1 g). Yield 700 mg. .sup.1H-NMR (400 MHz;
DMSO-d.sub.6): .delta. -0.01 (s, 9H), 0.83-0.94 (m, 6H), 2.01-2.08
(m, 1H), 3.52 (t, 2H), 5.43 (s, 2H), 7.82 (s, 1H), 12.26 (bs,
1H).
c)
(S)--N-(1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-
-yl)-2-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-car-
boxamide
The title compound was prepared using the procedure described in
Example 32(e) starting from
2-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carboxy-
lic acid (1.41 mmol, 400 mg) and
(S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-6-fluorobenzonitrile
(1.41 mmol, 395 mg). The product was purified by
flash-chromatography. Yield 249 mg. .sup.1H-NMR (400 MHz;
CDCl.sub.3): .delta. -0.01 (s, 9H), 0.93 (t, 2H), 0.99 (d, 4H),
1.23 (d, 3H), 1.88-1.95 (m, 1H), 3.52 (t, 2H), 4.29-4.40 (m, 2H),
4.47-4.54 (m, 1H), 5.33 (s, 2H), 6.59 (d, 1H), 7.35 (d, 1H),
7.49-7.51 (m, 2H), 7.58 (d, 1H), 7.72 (s, 1H).
d)
(S)--N-(1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-
-yl)-2-cyclopropyl-1H-imidazole-4-carboxamide
The title compound was prepared using the procedure described in
Example 52(h) starting from
(S)--N-(1-(3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-y-
l)-2-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carbo-
xamide (0.46 mmol, 250 mg). Yield 70 mg. .sup.1H-NMR (400 MHz;
DMSO-d.sub.6): .delta. 0.81-0.91 (m, 4H), 1.08 (d, 3H), 1.92-1.97
(m, 1H), 4.27-4.40 (m, 3H), 7.02 (bs, 1H), 7.38 (bs, 1H), 7.85-7.90
(m, 3H), 7.98 (s, 1H), 12.08 (s, 1H). LC-MS: [M+1]=413.19.
Example 71
(S)--N.sup.4-(1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propa-
n-2-yl)-N.sup.2,N.sup.2-dimethyl-1H-imidazole-2,4-dicarboxamide
a) 4-Benzyl 2-ethyl
1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-2,4-dicarboxylate
The title compound was prepared using the procedure described in
Example 52(d) starting from benzyl
2-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carboxylate
(0.609 mmol, 250 mg) and ethyl cyanoformate (0.91 mmol, 90 mg).
Yield 97 mg. .sup.1H-NMR (400 MHz; CDCl.sub.3): .delta. -0.08 (s,
9H), 0.91 (t, 2H), 1.42 (t, 3H), 3.57 (t, 2H), 4.43 (q, 2H), 5.38
(s, 2H), 5.78 (s, 2H), 7.30-7.39 (m, 3H), 7.43-7.46 (m, 2H), 7.90
(s, 1H). LC-MS: [M+1]=405.13.
b)
2-(Ethoxycarbonyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4--
carboxylic acid
The title compound was prepared using the procedure described in
Example 58(e) starting from 4-benzyl 2-ethyl
1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-2,4-dicarboxylate
(4.94 mmol, 2 g). Yield 1.61 g. .sup.1H-NMR (400 MHz;
DMSO-d.sub.6): .delta. -0.07 (s, 9H), 0.74 (t, 2H), 1.32 (t, 3H),
3.52 (t, 2H), 4.32 (q, 2H), 5.70 (s, 2H), 8.23 (s, 1H), 12.76 (bs,
1H). LC-MS: [M+1]=315.04.
c) (S)-Ethyl
4-((1-(3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-yl)ca-
rbamoyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-2-carboxylate
The title compound was prepared using the procedure described in
Example 32(e) starting from
2-(ethoxycarbonyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-ca-
rboxylic acid (3.18 mmol, 1 g) and
(S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-6-fluorobenzonitrile
(3.18 mmol, 890 mg). The product was purified by
flash-chromatography. Yield 1.6 g. .sup.1H-NMR (400 MHz;
DMSO-d.sub.6): .delta. -0.01 (s, 9H), 0.80 (t, 2H), 1.15 (d, 3H),
1.30 (t, 3H), 3.48 (t, 2H), 4.34-4.49 (m, 5H), 5.69 (s, 2H), 6.98
(d, 1H), 7.78-7.82 (m, 2H), 7.87 (s, 1H), 8.03 (s, 1H), 8.21 (d,
1H). LC-MS: [M+1]=575.11.
d)
(S)-4-((1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-
-yl)carbamoyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-2-carboxy-
lic acid
The title compound was prepared using the procedure described in
Example 32(d) starting from (S)-ethyl
4-((1-(3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-yl)ca-
rbamoyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-2-carboxylate
(5.22 mmol, 3 g) and sodium hydroxide (7.83 mmol, 313 mg). Yield
1.49 g. LC-MS: [M+1]=547.28.
e)
(S)--N.sup.4-(1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)pr-
opan-2-yl)-N.sup.2,N.sup.2-dimethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1-
H-imidazole-2,4-dicarboxamide
The title compound was prepared using the procedure described in
Example 32(e) starting from
(S)-4-((1-(3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-y-
l)carbamoyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-2-carboxyli-
c acid (0.549 mmol, 300 mg) and N,N-dimethylamine (0.824 mmol, 37
mg). The product was purified by flash-chromatography. Yield 207
mg. .sup.1H-NMR (400 MHz; CDCl.sub.3): .delta. -0.01 (s, 9H), 0.91
(t, 2H), 1.26 (d, 3H), 3.11 (s, 3H), 3.26 (s, 3H), 3.54 (t, 2H),
4.31-4.42 (m, 2H), 4.51-4.57 (m, 1H), 5.74 (s, 2H), 6.59 (d, 1H),
7.39 (d, 1H), 7.49 (d, 1H), 7.59 (d, 1H), 7.81 (s, 1H), 7.84 (s,
1H). LC-MS: [M+1]=574.32.
f)
(S)--N.sup.4-(1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)pr-
opan-2-yl)-N.sup.2,N.sup.2-dimethyl-1H-imidazole-2,4-dicarboxamide
The title compound was prepared using the procedure described in
Example 52(h) starting from
(S)--N.sup.4-(1-(3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)prop-
an-2-yl)-N.sup.2,N.sup.2-dimethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H--
imidazole-2,4-dicarboxamide (0.301 mmol, 200 mg). The product was
purified by flash-chromatography. Yield 87 mg. .sup.1H-NMR (400
MHz; DMSO-d.sub.6): .delta. 1.11 (d, 3H), 3.01 (s, 3H), 3.53 (s,
3H), 4.30-4.45 (m, 3H), 7.0 (d, 1H), 7.60 (d, 1H), 7.84-7.86 (m,
2H), 7.91-7.95 (m, 2H), 13.24 (s, 1H). LC-MS: [M+1]=444.12.
Example 72
(S)--N-(1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-yl-
)-2-(2-ethoxypropan-2-yl)-1H-imidazole-4-carboxamide
a) Methyl
2-(2-ethoxypropan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H--
imidazole-4-carboxylate and ethyl
2-(2-ethoxypropan-2-yl)-1-((2-(trimethylsilyl)-ethoxy)methyl)-1H-imidazol-
e-4-carboxylate
Into a flask containing methyl
2-(2-hydroxypropan-2-yl)-1-((2-(trimethyl-silyl)ethoxy)methyl)-1H-imidazo-
le-4-carboxylate (0.95 mmol, 300 mg) in DMF (3 ml), 60% sodium
hydride (2.86 mmol, 68 mg) was added in portions at 0.degree. C.
The reaction mixture was stirred for 10 min. EtI (1.91 mmol, 298
mg) was added and stirred at ambient temperature for 6 h. After
completion of the reaction, the mixture was quenched with H.sub.2O,
extracted with EtOAc. The organic layers were washed with water,
dried, filtered and evaporated. The crude was purified by
flash-chromatography. The LCMS showed the mixture of methyl
2-(2-ethoxypropan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-im-
idazole-4-carboxylate and ethyl
2-(2-ethoxypropan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-
-4-carboxylate. The mixture was preceded to the next step without
any further purification. Yield 90 mg (mixture). LC-MS:
[M+1]=343.42, [M+15]: 357.16.
b)
2-(2-Ethoxypropan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo-
le-4-carboxylic acid
The title compound was prepared using the procedure described in
Example 58(e) starting from the mixture of methyl
2-(2-ethoxypropan-2-yl)-1-((2-(trimethyl-silyl)ethoxy)methyl)-1H-imidazol-
e-4-carboxylate and ethyl
2-(2-ethoxypropan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-
-4-carboxylate (90 mg). Yield 70 mg. .sup.1H-NMR (400 MHz;
DMSO-d.sub.6): .delta. -0.02 (s, 9H), 0.87 (t, 2H), 1.06 (t, 3H),
1.57 (s, 6H), 3.12 (q, 2H), 3.58 (t, 2H), 5.53 (s, 2H), 7.93 (s,
1H), 12.28 (bs, 1H).
c)
(S)--N-(1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-
-yl)-2-(2-ethoxypropan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imida-
zole-4-carboxamide
The title compound was prepared using the procedure described in
Example 32(e) starting from
2-(2-ethoxypropan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-
-4-carboxylic acid (1.15 mmol, 380 g) and
(S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-6-fluorobenzonitrile
(1.15 mmol, 320 mg). The product was purified by
flash-chromatography. Yield 260 mg. .sup.1H-NMR (400 MHz;
DMSO-d.sub.6): .delta. -0.01 (s, 9H), 0.80-0.91 (m, 5H), 0.94 (t,
3H), 1.23 (s, 6H), 3.21 (q, 2H), 3.58 (t, 2H), 4.33-4.42 (m, 2H),
4.53-4.59 (m, 1H), 5.53 (s, 2H), 6.61 (d, 1H), 7.41 (d, 1H), 7.52
(d, 1H), 7.59 (d, 1H), 7.64 (s, 1H), 7.74 (s, 1H). LC-MS:
[M+1]=589.23.
d)
(S)--N-(1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-
-yl)-2-(2-ethoxypropan-2-yl)-1H-imidazole-4-carboxamide
The title compound was prepared using the procedure described in
Example 52(h) starting from
(S)--N-(1-(3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-y-
l)-2-(2-ethoxypropan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo-
le-4-carboxamide (0.39 mmol, 230 mg). The product was purified with
flash-chromatography. Yield 102 mg. .sup.1H-NMR (400 MHz;
DMSO-d.sub.6): .delta. 0.96 (t, 3H), 1.10 (d, 3H), 1.49 (s, 6H),
3.08 (q, 2H), 4.30-4.45 (m, 3H), 7.03 (bs, 1H), 7.51 (bs, 1H), 7.77
(d, 1H), 7.83-7.89 (m, 2H), 7.99 (s, 1H), 12.33 (bs, 1H). LC-MS:
[M+1]=459.34.
Example 73
N--((S)-1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-yl-
)-2-(1-ethoxyethyl)-1H-imidazole-4-carboxamide
a) Methyl
2-(1-hydroxyethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imida-
zole-4-carboxylate
The title compound was prepared using the procedure described in
Example 33(e) starting from methyl
2-acetyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carboxylate
(3.33 mmol, 1 g). Yield 970 mg. .sup.1H-NMR (400 MHz; CDCl.sub.3):
.delta. -0.01 (s, 9H), 0.86 (t, 2H), 1.66 (d, 3H), 2.92 (bs, 1H),
3.52 (t, 2H), 3.90 (s, 3H), 5.02 (m, 1H), 5.41 (q, 2H), 7.66 (s,
1H).
b) Methyl
2-(1-ethoxyethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidaz-
ole-4-carboxylate and ethyl
2-(1-ethoxyethyl)-1-((2-(trimethylsilyl)ethoxy)-methyl)-1H-imidazole-4-ca-
rboxylate
The mixture of the title compounds was prepared using the procedure
described in Example 72(a) starting from methyl
2-(1-hydroxyethyl)-1-((2-(trimethyl-silyl)ethoxy)methyl)-1H-imidazole-4-c-
arboxylate (1.66 mmol, 500 mg). Yield 230 mg (mixture). LC-MS:
[M+1]=329.21 [M+15]: 343.30.
c)
2-(1-Ethoxyethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-c-
arboxylic acid
The title compound was prepared using the procedure described in
Example 58(e) starting from the mixture of methyl
2-(1-ethoxyethyl)-1-((2-(trimethylsilyl)-ethoxy)methyl)-1H-imidazole-4-ca-
rboxylate and ethyl
2-(1-ethoxyethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-car-
boxylate (600 mg). Yield 370 mg. .sup.1H-NMR (400 MHz;
DMSO-d.sub.6): .delta. -0.01 (s, 9H), 0.86 (t, 2H), 1.08 (d, 3H),
1.45 (t, 3H), 3.41 (q, 2H), 3.50 (t, 2H), 4.71 (q, 1H), 5.42 (s,
2H), 7.92 (s, 1H), 12.13 (bs, 1H). LC-MS: [M+1]=315.12.
d)
N--((S)-1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-
-yl)-2-(1-ethoxyethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-
-carboxamide
The title compound was prepared using the procedure described in
Example 32(e) starting from
2-(1-ethoxyethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-car-
boxylic acid (1.27 mmol, 400 mg) and
(S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-6-fluorobenzonitrile
(1.27 mmol, 350 mg). The product was purified by
flash-chromatography. Yield 230 mg. LC-MS: [M+1]=575.28.
e)
N--((S)-1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-
-yl)-2-(1-ethoxyethyl)-1H-imidazole-4-carboxamide
The title compound was prepared using the procedure described in
Example 52(h) starting from
N--((S)-1-(3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-y-
l)-2-(1-ethoxyethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-c-
arboxamide (0.39 mmol, 230 mg). The product was purified by
flash-chromatography. Yield 97 mg. .sup.1H-NMR (400 MHz;
DMSO-d.sub.6): .delta. 1.01-1.09 (m, 6H), 1.40 (d, 3H), 3.22-3.40
(m, 2H), 4.27-4.45 (m, 3H), 4.51 (q, 1H), 7.0 (d, 1H), 7.51 (d,
1H), 7.83-8.04 (m, 4H), 12.47 (s, 1H). LC-MS: [M+1]=445.23.
Example 74
(S)--N-(1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-yl-
)-2-(2-ethoxypropan-2-yl)oxazole-4-carboxamide
a) Ethyl 2-(2-ethoxypropan-2-yl)oxazole-4-carboxylate
The title compound was prepared using the procedure described in
Example 72(a) starting from ethyl
2-(2-hydroxypropan-2-yl)oxazole-4-carboxylate (2.50 mmol, 500 mg).
The product was purified by flash-chromatography. Yield 260 mg.
.sup.1H-NMR (400 MHz; CDCl.sub.3): .delta. 1.13 (t, 3H), 1.38 (t,
3H), 1.66 (s, 6H), 3.27 (q, 2H), 4.39 (q, 2H), 8.21 (s, 1H).
b)
(S)--N-(1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-
-yl)-2-(2-ethoxypropan-2-yl)oxazole-4-carboxamide
The title compound was prepared using the procedure described in
Example 52(g) starting from ethyl
3-(2-hydroxypropan-2-yl)-1,2,4-oxadiazole-5-carboxylate (1.1 mmol,
250 mg) and
(S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-6-fluorobenzon-
itrile (1.1 mmol, 300 mg). Yield 86 mg. .sup.1H-NMR (400 MHz;
DMSO-d.sub.6): .delta. 1.0 (t, 3H), 1.12 (d, 3H), 1.55 (s, 6H),
3.16 (q, 2H), 4.29-4.49 (m, 3H), 7.02 (d, 1H), 7.84-7.87 (m, 2H),
7.98 (s, 1H), 8.15 (d, 1H), 8.55 (s, 1H). LC-MS: [M+1]=460.05.
Example 75
(S)--N-(1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-yl-
)-5-(2-hydroxy-2-methylpropyl)-1H-pyrazole-3-carboxamide
a) Ethyl 5-(2-hydroxypropyl)-1H-pyrazole-3-carboxylate
Into a flask containing ethyl diazoacetate (52.63 mmol, 6 g) in
toluene (100 ml), 3-butyn-2-ol (78.94 mmol, 6.6 g) was added at RT
and stirred at 100.degree. C. for 5 h. The solvent was evaporated
and the crude was purified by flash-chromatography. Yield 697 mg.
.sup.1H-NMR (400 MHz; CDCl.sub.3): .delta. 1.22-1.28 (m, 3H), 1.39
(t, 3H), 2.72-2.78 (m, 1H), 2.82-2.91 (m, 1H), 4.10-4.17 (m, 1H),
4.38 (q, 2H), 6.64 (s, 1H).
b) Ethyl
5-(2-hydroxypropyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyraz-
ole-3-carboxylate
Into a flask containing ethyl
5-(2-hydroxypropyl)-1H-pyrazole-3-carboxylate (15.65 mmol, 3.2 g)
in acetone (60 ml), Cs.sub.2CO.sub.3 (13.7 g, 99.1 mmol), SEM-Cl
(9.3 ml, 51.6 mmol) were added and stirred at RT overnight. The
reaction mixture was quenched by the addition of H.sub.2O and
extracted with EtOAc. The organic layer was concentrated and
purified by column-chromatography. Yield 3.8 g. .sup.1H-NMR (400
MHz; CDCl.sub.3): .delta. -0.05 (s, 9H), 0.89 (t, 2H), 1.25 (d,
3H), 1.40 (t, 3H), 2.71-2.83 (m, 3H), 3.57 (t, 2H), 4.34 (q, 2H),
5.79 (s, 2H), 6.74 (s, 1H). LC-MS: [M+1]=329.14.
c) Ethyl
5-(2-oxopropyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole--
3-carboxylate
The title compound was prepared using the procedure described in
Example 68(a) starting from ethyl
5-(2-hydroxypropyl)-1H-pyrazole-3-carboxylate (8.84 mmol, 2.9 g).
Yield 3.8 g. .sup.1H-NMR (400 MHz; CDCl.sub.3): .delta. -0.05 (s,
9H), 0.89 (t, 2H), 1.36 (t, 3H), 2.18 (s, 3H), 3.57 (t, 2H), 3.76
(s, 2H), 4.34 (q, 2H), 5.80 (s, 2H), 6.82 (s, 1H). LC-MS:
[M+1]=327.26.
d) Ethyl
5-(2-hydroxy-2-methylpropyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-
-1H-pyrazole-3-carboxylate
The title compound was prepared using the procedure described in
Example 2(d) starting from ethyl
5-(2-oxopropyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-3-carbox-
ylate (5.24 mmol, 1.7 g) and 3 M solution of MeMgI in ether (6.78
mmol, 2.2 ml). Yield 301 mg. .sup.1H-NMR (400 MHz; CDCl.sub.3):
.delta. -0.05 (s, 9H), 0.89 (t, 2H), 1.24 (s, 6H), 1.38 (t, 3H),
2.76 (s, 2H), 3.57 (t, 2H), 4.34 (q, 2H), 5.81 (s, 2H), 6.76 (s,
1H).
e)
5-(2-Hydroxy-2-methylpropyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-py-
razole-3-carboxylic acid
The title compound was prepared using the procedure described in
Example 32(d) starting from ethyl
5-(2-hydroxy-2-methylpropyl)-1-((2-(trimethylsilyl)ethoxy)-methyl)-1H-pyr-
azole-3-carboxylate (1.9 mmol, 650 mg). Yield 1.49 g. .sup.1H-NMR
(400 MHz; DMSO-d.sub.6): .delta. -0.01 (s, 9H), 0.77 (t, 2H), 1.07
(s, 6H), 2.64 (s, 2H), 3.57 (t, 2H), 4.42 (bs, 1H), 5.76 (s, 2H),
6.74 (s, 1H), 12.60 (bs, 1H). LC-MS: [M+1]=315.07.
f)
(S)--N-(1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-
-yl)-5-(2-hydroxy-2-methylpropyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H--
pyrazole-3-carboxamide
The title compound was prepared using the procedure described in
Example 32(e) starting from
5-(2-hydroxy-2-methylpropyl)-1-((2-(trimethylsilyl)ethoxy)-methyl)-1H-pyr-
azole-3-carboxylic acid (1.59 mmol, 500 mg) and
(S)-4-(1-(2-amino-propyl)-1H-pyrazol-3-yl)-2-chloro-6-fluorobenzonitrile
(1.59 mmol, 442 mg). The product was purified by
flash-chromatography. Yield 295 mg. .sup.1H-NMR (400 MHz;
DMSO-d.sub.6): .delta. -0.13 (s, 9H), 0.68 (t, 2H), 1.06 (s, 3H),
1.08 (s, 3H), 1.20 (d, 3H), 2.61 (s, 2H), 3.40 (t, 2H), 4.23-4.42
(m, 3H), 4.51 (s, 1H), 5.54 (d, 1H), 5.68 (d, 1H), 6.72 (s, 1H),
7.01 (d, 1H), 7.84-7.87 (m, 2H), 7.96 (s, 1H), 8.40 (d, 1H). LC-MS:
[M+1]=575.01.
g)
(S)--N-(1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-
-yl)-5-(2-hydroxy-2-methylpropyl)-1H-pyrazole-3-carboxamide
The title compound was prepared using the procedure described in
Example 52(h) starting from
(S)--N-(1-(3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-y-
l)-5-(2-hydroxy-2-methylpropyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-py-
razole-3-carboxamide (0.514 mmol, 295 mg). The product was purified
by flash-chromatography. Yield 85 mg. .sup.1H-NMR (400 MHz;
DMSO-d.sub.6): .delta. 1.06 (s, 6H), 1.13 (d, 3H), 2.67 (s, 2H),
4.25-4.48 (m, 3H), 4.51 (s, 1H), 6.34 (s, 1H), 7.0 (d, 1H),
7.83-7.88 (m, 2H), 7.96 (d, 1H), 8.28 (d, 1H), 12.78 (s, 1H).
LC-MS: [M+1]=445.18.
ABBREVIATIONS
ACN--Acetonitrile
AIBN--Azobisisobutyronitrile
(Boc).sub.2O--Di-t-butyl dicarbonate
DCM--Dichloromethane
DIAD--Di-tert-butyl azodicarboxylate
DIPEA--N,N-diisopropylethylamine
DME--Ethylene glycol dimethyl ether
DMF--N,N-Dimethylformamide
DMSO--Dimethylsulfoxide
DMAP--4-Dimethylaminopyridine
Dppf--1,1'-bis(diphenylphosphanyl) ferrocene
EDCI--1-(3-Dimethylaminopropyl)-3-ethylcarbodi-imide hydrochloride
EtOAc--Ethyl acetate EtOH--Ethanol
HBTU--O-(benzotriazol-1-yl)-N,N,N',N''-tetramethyluroniumhexafluorophosph-
ate HOBt--1-Hydroxybenzotriazole MeOH--Methanol
MTBE--Methyl-tert-butyl ether NBS--N-bromosuccinimide
NMP--N-methylpyrrolidone RT--Room temperature
SEM-Cl--2-(Trimethylsilyl)ethoxymethyl chloride
TBME--tert-Butylmethyl ether
TBDMSCl--tert-Butyldimethylchlorosilane THF--Tetrahydrofuran
* * * * *